1,4-disubstituted piperidines as vasopressin receptor via antagonists

ABSTRACT

The present invention provides compounds of formula (1) compositions comprising such compounds; the use of such compounds in therapy (such as in the treatment of dysmenorrhoea); and methods of treating patients with such compounds; wherein A and G are as defined herein.

This invention relates to V_(1a) antagonists and to processes for thepreparation of, intermediates used in the preparation of, compositionscontaining and the uses of, such derivatives.

BACKGROUND

The neurophyseal hormones vasopressin (VP) and oxytocin (OT) are cyclicnonapeptides secreted by the posterior pituitary gland.

Only one OT receptor has so far been well characterised, while three VPreceptors are known. These are designated the V_(1a), V_(1b) and V₂receptors.

Vasopressin acts on the blood vessels, where it is a potentvasoconstrictor, and on the kidneys, where it promotes water reuptakeleading to an antidiuretic effect.

The V_(1a), V_(1b), and V₂, as well as the OT receptors, are members ofthe super-family of seven transmembrane receptors known as G-proteincoupled receptors. The V_(1a) receptor mediates phospholipase Cactivation and intracellular calcium mobilisation. Localisation of thereceptors includes blood platelets, blood vessels, hepatocytes, brainand uterus-cervix. Thus a V_(1a) antagonist may have effects on any orall of these tissues. For example, selective V_(1a) antagonists havebeen cited as having clinical utility in dysmenorrhoea, pre-term labour,hypertension, Raynaud's disease, brain oedema, motion sickness,hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia,liver cirrhosis and congestive heart failure.

With respect to dysmenorrhoea it has been proposed that myometrialactivity is markedly increased in women with dysmenorrhoea duringmenstruation. It is proposed that the myometrial ischemia caused byincreased uterine contractility might explain the menstrual pain.Furthermore, on the first day of menstruation, higher plasmaconcentrations of vasopressin have been measured in dysmenorroeic womenthan in controls.

In healthy women without dysmenorrhoea, intravenous in-fusion oflysine-vasopressin resulted in decreased uterine blood flow, increaseduterine contractility and slight to moderate dysmenorrhoea-like pain,these effects being inhibited by a selective human V_(1a) receptorantagonist (British Journal of Obstetrics And Gynaecology 1997, 104(4),471). Also, it is known that vasopressin contracts human uterinearteries in a dose-dependent and V_(1a)-mediated fashion.

The above evidence suggests that a V_(1a) antagonist would be anappropriate and effective treatment for dysmenorrhoea (primarydysmenorrhoea and/or secondary dysmenorrhoea). Further evidence is takenfrom the clinical study carried out on the selective V_(1a) antagonistSR49059 (Brouard, R. et al. British Journal of Obstetrics andGynaecology 2000, 107(5), 614. It was found that there was adose-related decrease in pain and a dose-related decrease in the amountof additional pain-killer taken compared to patients taking placebo.

WO 03/016316 A1 describes a number of compounds which are claimed to beoxytocin agonists and to find use in the treatment of male erectiledysfunction. No V_(1a) antagonist activity is reported.

EP 1 449 844 A1 describes a number of compounds which are claimed to beV_(1a) antagonists and to find use in the treatment of primarydysmenorrhoea.

WO 2006/021213 A2 describes compounds which are V_(1a) antagonists andfind use in the treatment of primary dysmenorrhoea.

There exists a need for treatments for conditions which are associatedwith the V_(1a) receptors. Therefore, there continues to be a need foralternative V_(1a) antagonists.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a compound of formula (1):

wherein,G is a fused azepine selected from formula (2), (3), or (4),

wherein,R¹ is H, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl,(C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-;R² is (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl- orheteroaryl(C₁-C₄)alkyl-;R³ is H, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl,(C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-;R⁴ is (C₁-C₁₀)alkyl, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl- orheteroaryl(C₁-C₄)alkyl-;R⁵ is H, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl,(C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-; andA is phenyl or a 5- or 6-membered aromatic ring containing 1, 2 or 3 Natoms, wherein said phenyl or said 5- or 6-membered ring are optionallysubstituted with 1 to 3 substituents independently chosen from the groupconsisting of halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl,(C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl-, heteroaryl(C₁-C₄)alkyl-, CF₃, CN, NO₂, OH, CO₂R^(d)and NR^(d)R^(e), wherein

-   -   each alkyl may independently be optionally substituted with 1 or        2 substituents independently selected from (C₃-C₁₀)cycloalkyl,        (C₁-C₆)alkoxy, OH, CN, CF₃, CO₂R^(p), halo and NR^(p)R^(q);    -   each alkenyl may independently be optionally substituted with 1        or 2 substituents independently selected from        (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, CO₂R^(r), halo        and NR^(r)R^(s);    -   each alkoxy may independently be optionally be substituted with        1 or 2 substituents independently selected from        (C₃-C₁₀)cycloalkyl, OH, CN, CF₃, CO₂R^(t), halo and NR^(t)R^(u);    -   each cycloalkyl is independently a non-aromatic mono- or bicylic        hydrocarbon ring, optionally fused to an aryl group, wherein        said cycloalkyl ring may optionally contain up to 2 double        bonds; and wherein, unless otherwise stated, said cycloalkyl may        optionally be substituted with 1 or 2 substituents independently        selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃,        CO₂R^(v), halo and NR^(v)R^(w);    -   each heterocycloalkyl is independently a C-linked or N-linked        non-aromatic, 3-10 membered mono- or bicyclic ring, wherein said        heterocycloalkyl ring may contain 1, 2 or 3 ring members        independently selected from N, NR^(x), S(O)_(y) and O; and said        heterocycloalkyl ring may optionally contain 1 or 2 double        bonds, and is optionally substituted on carbon with 1 or 2        substituents independently selected from (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, OH, CN, CF₃, halo, CO₂R^(x), NR^(x)R^(y) and        aryl;    -   aryl is a 6 or 10 membered aromatic mono- or bicyclic ring        system; wherein, unless otherwise stated, each occurrence of        aryl may be optionally substituted with up to 5 substituents        independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH,        halo, CN, CO₂R^(a), CF₃ and NR^(a)R^(z);    -   heteroaryl is a 5, 6, 9 or 10 membered aromatic mono- or        bicyclic ring system, containing 1 or 2 N atoms and, optionally,        an NR^(b) ring member, an S or an O atom; or containing one        NR^(b) ring member and an S or an O atom; or containing one        NR^(b) ring member; or containing one S atom; or containing one        O atom; wherein, unless otherwise stated, said heteroaryl may be        optionally substituted with 1, 2 or 3 substituents independently        selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, halo, CN,        CO₂R^(b), CF₃ and NR^(b)R^(c); wherein    -   R^(p), R^(q), R^(r), R^(s), R^(t), R^(u), R^(x), R^(y), R^(a),        R^(z), R^(b), R^(c), R^(d) and R^(e) are each independently        selected from H and (C₁-C₆)alkyl; and    -   y is 0, 1 or 2;        and pharmaceutically acceptable salts and solvates thereof.

In an aspect the present invention provides a prodrug of a compound offormula (I) as herein defined, or a pharmaceutically acceptable saltthereof.

In an aspect the present invention provides an N-oxide of a compound offormula (I) as herein defined, or a prodrug or pharmaceuticallyacceptable salt thereof.

It will be understood that certain compounds of the present inventionmay exist in solvated, for example hydrated, as well as unsolvatedforms. It is to be understood that the present invention encompasses allsuch solvated forms.

In an aspect the present invention provides a compound of formula (1),wherein:

R¹ is H, halo or (C₁-C₆)alkyl;R² is (C₁-C₆)alkyl, aryl, heterocycloalkyl or aryl(C₁-C₄)alkyl-;R³ is H, halo or (C₁-C₆)alkyl;R⁴ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₄)alkyl-;R⁵ is H, halo or (C₁-C₆)alkyl;

A is

-   -   wherein        R⁷ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CN, CH₂NH₂, NO₂ or        NH₂;        R⁸ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CN, NO₂, CF₃ or Ph;        and        R⁹ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CN, CH₂NH₂, NO₂, NH₂        or CF₃;        wherein G, alkyl, alkoxy, aryl and heterocycloalkyl are as        previously defined;        and pharmaceutically acceptable salts and solvates thereof.

In an aspect the present invention provides a compound of formula (1),wherein:

R¹ is H, F, Cl or Me;

R² is Me, Et, n-Pr, n-Bu, i-Bu, cyclopropyl, cyclohexyl, phenyl,(2-fluoro)-phenyl, (3-fluoro)-phenyl, benzyl, tetrahydropyranyl,pyrrolidinyl, piperidinyl, morpholinyl or N-methylpiperazinyl;

R³ is H, F, Cl or Me;

R⁴ is Me, Et, t-butyl, cyclohexyl, phenyl or benzyl;

R⁵ is H, F or Me; R⁶ is H, F, Cl, Me, OMe, CN, CH₂NH₂, NO₂ or NH₂; R⁷ isH, F, Cl, Me, OMe, CN, NO₂, CF₃ or Ph; and

R⁸ is H, F, Cl, Me, OMe, CN, CH₂NH₂, NO₂, NH₂, CF₃, Et, n-Pr or i-Pr;wherein G is as previously defined;and pharmaceutically acceptable salts and solvates thereof.

The present invention additionally comprises the following aspects:

i) A compound of formula (1), as previously defined, wherein G is afused azepine of general formula 2.ii) A compound of formula (1), as previously defined, wherein G is afused azepine of general formula 3.iii) A compound of formula (1), as previously defined, wherein G is afused azepine of general formula 4.iv) A compound of formula (1), as defined in aspect i), wherein R¹ is H,halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, aryl oraryl(C₁-C₄)alkyl-.v) A compound of formula (1), as defined in aspect i), wherein R¹ is H,halo or (C₁-C₆)alkyl.vi) A compound of formula (1), as defined in aspect i), wherein R¹ is H,F, Cl or Me.vii) A compound of formula (1), as defined in aspect i), wherein R¹ is For Me.viii) A compound of formula (1), as defined in any one of aspects i) andiv)-vii), wherein R² is (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, aryl(C₁-C₄)alkyl- orheteroaryl(C₁-C₄)alkyl-.ix) A compound of formula (1), as defined in any one of aspects i) andiv)-vii), wherein R² is (C₁-C₆)alkyl, aryl, heterocycloalkyl oraryl(C₁-C₄)alkyl-.x) A compound of formula (1), as defined in any one of aspects i) andiv)-vii), wherein R² is Me, Et, n-Pr, n-Bu, i-Bu, cyclopropyl,cyclohexyl, phenyl, (2-fluoro)-phenyl, (3-fluoro)-phenyl, benzyl,tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl orN-methylpiperazinyl.xi) A compound of formula (1), as defined in any one of aspects i) andiv)-vii), wherein R² is Me, Et, n-Pr, n-Bu, i-Bu, cyclopropyl,cyclohexyl, benzyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,morpholinyl or N-methylpiperazinyl.xii) A compound of formula (1), as defined in any one of aspects i) andiv)-vii), wherein R² is morpholinyl.xiii) A compound of formula (1), as defined in aspect ii), wherein R³ isH, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, aryl oraryl(C₁-C₄)alkyl-.xiv) A compound of formula (1), as defined in aspect ii), wherein R³ isH, halo or (C₁-C₆)alkyl.xv) A compound of formula (1), as defined in aspect ii), wherein R³ isH, F, Cl or Me.xvi) A compound of formula (1), as defined in any one of aspects ii) andxiii)-xv), wherein R⁴ is (C₁-C₁₀)alkyl, (C₃-C₁₀)cycloalkyl,heterocycloalkyl, aryl, aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-.xvii) A compound of formula (1), as defined in any one of aspects ii)and xiii)-xv), wherein R⁴ is (C₁-C₆)alkyl, aryl or aryl(C₁-C₄)alkyl-.xviii) A compound of formula (1), as defined in any one of aspects ii)and xiii)-xv), wherein R⁴ is Me, Et, t-butyl, cyclohexyl, phenyl orbenzyl.xix) A compound of formula (1), as defined in aspect iii), wherein R⁵ isH, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, aryl oraryl(C₁-C₄)alkyl-.xx) A compound of formula (1), as defined in aspect iii), wherein R⁵ isH, halo or (C₁-C₆)alkyl.xxi) A compound of formula (1), as defined in aspect iii), wherein R⁵ isH, F or Me.xxii) A compound of formula (1), as defined in any one of the previousaspects, wherein A is a phenyl or a 6-membered aromatic ring containing1, 2 or 3 N atoms and wherein said phenyl or said 6-membered ring areoptionally substituted with 1 to 3 substituents independently chosenfrom the group consisting of halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy,(C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl-, heteroaryl(C₁-C₄)alkyl-, CF₃, CN, NO₂, OH, CO₂R^(d)and NR^(d)R^(e), wherein R^(d) and R^(e) are as previously defined.xxiii) A compound of formula (1), as defined in aspect xxii), wherein Ais selected from the group consisting of:

wherein m is 0, 1 or 2; and n is independently 0, 1, 2 or 3, whereinwhen present, each R⁶ is independently selected from halo,(C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl-,heteroaryl(C₁-C₄)alkyl-, CF₃, CN, NO₂, OH, CO₂R^(d) and NR^(d)R^(e),wherein R^(d) and R^(e) are as previously defined.xxiv) A compound of formula (1), as defined in aspect xxiii), whereineach R⁶ is independently selected from halo, (C₁-C₁₀)alkyl,(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, aryl, aryl(C₁-C₄)alkyl-, CN, CF₃, NO₂and NH₂.xxv) A compound of formula (1), as defined in aspect xxiii), whereineach R⁶ is independently selected from H, F, Cl, Me, Et, n-Pr, i-Pr,OMe, CN, CH₂NH₂, NO₂ or NH₂, CF₃ or Ph.xxvi) A compound of formula (1), as defined in aspect xxiii), whereineach R⁶ is independently selected from H, Me or OMe.xxvii) A compound of formula (1), as defined in aspect xxii), wherein Ais selected from the group consisting of:

wherein each R⁷, R⁸ and R⁹ is independently selected from the groupconsisting ofH, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl,(C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl-, heteroaryl(C₁-C₄)alkyl-, CF₃, CN, NO₂, OH, CO₂R^(d)and NR^(d)R^(e), wherein R^(d) and R^(e) are as previously defined.xxviii) A compound of formula (1), as defined in aspect xxvii), whereinA is selected from the group consisting of

xxix) A compound of formula (1), as defined in aspect xxvii) or aspectxxviii), wherein R⁷ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, aryl, aryl(C₁-C₄)alkyl-, CF₃, CN, NO₂ or NH₂.xxx) A compound of formula (1), as defined in aspect xxvii) or aspectxxviii), wherein R⁷ is H, F, Cl, Me, OMe, CN, CH₂NH₂, NO₂ or NH₂.xxxi) A compound of formula (1), as defined in aspect xxvii) or aspectxxviii), wherein R⁷ is H, Me or OMe.xxxii) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxi), wherein R⁸ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, aryl, aryl(C₁-C₄)alkyl-, CF₃, CN, NO₂ or NH₂.xxxiii) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxi), wherein R⁸ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CN,NO₂, CF₃ or Ph.xxxiv) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxi), wherein R⁸ is H, F, Cl, Me, OMe, CN, NO₂, CF₃ or Ph.xxxv) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxi), wherein R⁸ is H, Me or OMe.xxxvi) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxv), wherein R⁹ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, aryl, aryl(C₁-C₄)alkyl-, CN, NO₂ or NH₂.xxxvii) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxv), wherein R⁹ is H, F, Cl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CF₃,CN, NO₂ or NH₂.xxxviii) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxv), wherein R⁹ is H, halo, Me, OMe, CN, CH₂NH₂, NO₂, NH₂, CF₃,Et, n-Pr, or i-Pr.xxxix) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxv), wherein R⁹ is H, Me or OMe.xl) A compound of formula (1), as defined in any one of aspectsxxiii)-xxvi), wherein m and n are each 1.xli) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxix), wherein R⁸ and R⁹ are each H when R⁷ is not H.xlii) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxix), wherein R⁷ and R⁸ are each H when R⁹ is not H.xliii) A compound of formula (1), as defined in any one of aspectsxxvii)-xxxix), wherein R⁷ and R⁹ are each H when R⁸ is not H.xliv) A compound of formula (1), as defined in aspect xxvii) or xxviii),wherein at least one of R⁷-R⁹ is H.xlv) A compound of formula (1), as defined in aspect xxvii) or xxviii),wherein R⁷-R⁹ are each H.xlvi) A compound of formula (1), as defined in aspect xxii), wherein Ais selected from the group consisting of:

In an aspect, the present invention provides a compound of formula (1)selected from the group consisting of:

-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)methanone;-   (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone;-   (2-Morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone;-   (4′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone;-   (5′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone;-   (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Ethyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-propyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-propyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Cyclopropyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Cyclopropyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Butyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Butyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Isobutyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Isobutyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   [9-Methyl-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(5′-methyl-3,4,5,6-tetrahydro-2[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (4′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone;-   (5′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone;-   (4′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone;-   (5′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone;-   (3′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone;-   (4′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone;-   (5′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone;-   (9-Methyl-2-pyrrolidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-ethyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-cyclopropyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-cyclohexyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-piperidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   [9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   [9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (2-Benzyl-9-chloro-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone;-   (2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone;-   (6′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone;-   (6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone;-   (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-ethyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-cyclopropyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-cyclohexyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-piperidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   [9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(1-phenyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-fluoro-phenyl)-piperidin-4-yl]-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(2-chloro-phenyl)-piperidin-4-yl]-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-chloro-phenyl)-piperidin-4-yl]-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-o-tolyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-m-tolyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-p-tolyl-piperidin-4-yl)-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-propyl-phenyl)-piperidin-4-yl]-methanone;-   (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-isopropyl-phenyl)-piperidin-4-yl]-methanone;-   (6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone;-   (6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-methanone;-   (3-Methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3-Ethyl-6-fluoro-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3-tert-Butyl-6-fluoro-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3-Benzyl-6-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahyciro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-m-tolyl-piperidin-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo    azulen-9-yl)-(1-p-tolyl-piperidin-4-yl)-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-m-tolyl-piperidin-4-yl)-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-p-tolyl-piperidin-4-yl)-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;-   (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone;-   (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo    azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-pyrazin-2-yl-piperidin-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   (7-Fluoro-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2,1-[1,2′]bipyridinyl-4-yl)-methanone;-   (7-Fluoro-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   (7-Methyl-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (7-Methyl-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-fluoro-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-fluoro-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-chloro-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-chloro-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-o-tolyl-piperidin-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-m-tolyl-piperidin-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-p-tolyl-piperidin-4-yl)-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-propyl-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-isopropyl-phenyl)-piperidin-4-yl]-methanone;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;-   3-[4-(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-piperidin-1-yl]-benzonitrile;-   (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-nitro-phenyl)-piperidin-4-yl]-methanone;-   [1-(2-Amino-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone;-   [1-(4-Amino-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone;-   [1-(2-Aminomethyl-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone;    and pharmaceutically acceptable salts or solvates thereof.

In an aspect, the present invention provides a compound of formula (1)selected from the group consisting of:

-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;-   (3′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)methanone;-   (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone;    and-   (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone;    and pharmaceutically acceptable salts or solvates thereof.

The skilled person will appreciate that each of the compounds identifiedabove, or identified in the Examples provided herein below, taken aloneor with any combination of the other identified compounds represents anindependent aspect of the invention.

Therapeutic Applications

As previously mentioned, the compounds of the present invention have anumber of therapeutic applications, particularly in the treatment ofdiseases or conditions mediated by vasopressin V_(1a).

Accordingly, the present invention provides a compound of formula (1),or a pharmaceutically acceptable salt or solvate thereof, for use intherapy.

The present invention also provides for the use of a compound of formula(1) in the manufacture of a medicament for the treatment of a disease orcondition mediated by vasopressin V_(1a) receptors.

The present invention also provides a compound of formula (1) for use inthe treatment of a disease or condition mediated by vasopressin V_(1a)receptors.

The present invention also provides a method of treatment of a diseaseor condition mediated by vasopressin V_(1a) receptors.

In an aspect, the disease or condition mediated by vasopressin V_(1a)receptors is selected from dysmenorrhoea (primary dysmenorrhoea and/orsecondary dysmenorrhoea), pre-term labour, hypertension, Raynaud'sdisease, brain oedema, motion sickness, hyperlipemia, small cell lungcancer, depression, anxiety, hyponatremia, liver cirrhosis andcongestive heart failure.

In an aspect, the disease or condition mediated by vasopressin V_(1a)receptors is dysmenorrhoea (primary dysmenorrhoea and/or secondarydysmenorrhoea).

DEFINITIONS

The term “alkyl” includes saturated hydrocarbon residues including:

-   -   linear groups up to 10 atoms (C₁-C₁₀), or of up to 6 atoms        (C₁-C₆), or of up to 4 atoms (C₁-C₄). Examples of such alkyl        groups include, but are not limited, to C₁-methyl, C₂-ethyl,        C₃-propyl and C₄-n-butyl.    -   branched groups of between 3 and 10 atoms (C₃-C₁₀), or of up to        7 atoms (C₃-C₇), or of up to 4 atoms (C₃-C₄). Examples of such        alkyl groups include, but are not limited to, C₃-iso-propyl,        C₄-sec-butyl, C₄-iso-butyl, C₄-tert-butyl and C₅-neo-pentyl.        each optionally substituted as stated above.

The term “alkenyl” includes monounsaturated hydrocarbon residuesincluding:

-   -   linear groups of between 2 and 6 atoms (C₂-C₆). Examples of such        alkenyl groups include, but are not limited to, C₂-vinyl,        C₃-1-propenyl, C₃-allyl, C₄-2-butenyl    -   branched groups of between 3 and 8 atoms (C₃-C₈). Examples of        such alkenyl groups include, but are not limited to,        C₄-2-methyl-2-propenyl and C₆-2,3-dimethyl-2-butenyl.        each optionally substituted as stated above.

The term “alkoxy” includes O-linked hydrocarbon residues including:

-   -   linear groups of between 1 and 6 atoms (C₁-C₆), or of between 1        and 4 atoms (C₁-C₄). Examples of such alkoxy groups include, but        are not limited to, C₁-methoxy, C₂-ethoxy, C₃-n-propoxy and        C₄-n-butoxy.    -   branched groups of between 3 and 6 atoms (C₃-C₆) or of between 3        and 4 atoms (C₃-C₄). Examples of such alkoxy groups include, but        are not limited to, C₃-iso-propoxy, and C₄-sec-butoxy and        tert-butoxy.        each optionally substituted as stated above.

Unless otherwise stated, halo is selected from Cl, F, Br and I.

Cycloalkyl is as defined above. Conveniently cycloalkyl groups maycontain from 4 to 10 carbon atoms, or from 5 to 10 carbon atoms, or from4 to 6 carbon atoms. Examples of suitable monocyclic cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentene, cyclopenta-1,3-diene, cyclohexene and cyclohexa-1,4-diene(optionally substituted as stated above). Examples of suitable bicycliccycloalkyl groups include decahydronaphthalene, octahydro-1H-indene(optionally substituted as stated above). Examples of suitablecycloalkyl groups, when fused with aryl, include indanyl and1,2,3,4-tetrahydronaphthyl (optionally substituted as stated above).

Heterocycloalkyl is as defined above. Examples of suitableheterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl,tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,N-methylpiperidinyl, morpholinyl, N-methyl morpholinyl, thiomorpholinyl,thiomorpholinyl-1-oxide, thiomorpholinyl-1,1-dioxide, piperazinyl,N-methylpiperazinyl, azepinyl oxazepinyl, diazepinyl, and1,2,3,4-tetrahydropyridinyl (optionally substituted as stated above).

Aryl is as defined above. Typically, aryl will be optionally substitutedwith 1, 2 or 3 substituents. Optional substituents are seleted fromthose stated above. Examples of suitable aryl groups include phenyl andnaphthyl (each optionally substituted as stated above).

Heteroaryl is as defined above. Examples of suitable heteroaryl groupsinclude thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl andisoquinolinyl (optionally substituted as stated above).

Alternatively, heteroaryl is a 5, 6, 9 or 10 membered aromatic mono- orbicyclic ring system, containing 1 or 2 N atoms and, optionally, anNR^(b) ring member, or one NR^(b) ring member and an S or an O atom, orone S atom, or one O atom; wherein, unless otherwise stated, saidheteroaryl may be optionally substituted with 1, 2 or 3 substituentsindependently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, halo, CN,CO₂R^(b), CF₃ and NR^(b)R^(c).

The term “C-linked”, such as in “C-linked heterocycloalkyl”, means thatthe heterocycloalkyl group is joined to the remainder of the moleculevia a ring carbon atom.

The term “N-linked”, such as in “N-linked heterocycloalkyl”, means thatthe heterocycloalkyl group is joined to the remainder of the moleculevia a ring nitrogen atom.

The term “O-linked”, such as in “O-linked hydrocarbon residue”, meansthat the hydrocarbon residue is joined to the remainder of the moleculevia an oxygen atom.

In groups such as aryl(C₁-C₄)alkyl-, “-” denotes the point of attachmentof the group to the remainder of the molecule.

“Pharmaceutically acceptable salt” means a physiologically ortoxicologically tolerable salt and includes, when appropriate,pharmaceutically acceptable base addition salts and pharmaceuticallyacceptable acid addition salts. For example (i) where a compound of theinvention contains one or more acidic groups, for example carboxygroups, pharmaceutically acceptable base addition salts that can beformed include sodium, potassium, calcium, magnesium and ammonium salts,or salts with organic amines, such as, diethylamine, N-methyl-glucamine,diethanolamine or amino acids (e.g. lysine) and the like; (ii) where acompound of the invention contains a basic group, such as an aminogroup, pharmaceutically acceptable acid addition salts that can beformed include hydrochlorides, hydrobromides, sulfates, phosphates,acetates, citrates, lactates, tartrates, mesylates, succinates,oxalates, phosphates, esylates, tosylates, benzenesulfonates,naphthalenedisulphonates, maleates, fumarates, hippurates, xinafoates,p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates,succinates, ascorbates, oleates, bisulfates and the like.

Hemisalts of acids and bases can also be formed, for example,hemisulfate and hemicalcium salts.

For a review of suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

“Prodrug” refers to a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis, reduction or oxidation) to a compound of theinvention. Suitable groups for forming pro-drugs are described in ‘ThePractice of Medicinal Chemistry, 2^(nd) Ed. pp 561-585 (2003) and in F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.

The compounds of the invention can exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when the solvent is water.

Where compounds of the invention exist in one or more geometrical,optical, enantiomeric, diastereomeric and tautomeric forms, includingbut not limited to cis- and trans-forms, E- and Z-forms, R-, S- andmeso-forms, keto-, and enol-forms. Unless otherwise stated a referenceto a particular compound includes all such isomeric forms, includingracemic and other mixtures thereof. Where appropriate such isomers canbe separated from their mixtures by the application or adaptation ofknown methods (e.g. chromatographic techniques and recrystallisationtechniques). Where appropriate such isomers can be prepared by theapplication or adaptation of known methods (e.g. asymmetric synthesis).

In the context of the present invention, references herein to“treatment” include references to curative, palliative and prophylactictreatment.

General Methods

The compounds of formula (I) should be assessed for theirbiopharmaceutical properties, such as solubility and solution stability(across pH), permeability, etc., in order to select the most appropriatedosage form and route of administration for treatment of the proposedindication.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallization, freeze drying, spray drying, evaporativedrying, melt congealing and extrusion. Conventional drying processesincluding static/dynamic oven, infrared, microwave or radio frequencydrying may be used to assist in the formation of the above crystallineand amorphous products.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof). Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients. The term “excipient” is usedherein to describe any ingredient other than the compound(s) of theinvention which may impart either a functional (i.e., drug release ratecontrolling) and/or a non-functional (i.e., processing aid or diluent)characteristic to the formulations. The choice of excipient will to alarge extent depend on factors such as the particular mode ofadministration, the effect of the excipient on solubility and stability,and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in Remington'sPharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Accordingly, the present invention provides a pharmaceutical compositioncomprising a compound of formula (1), or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier,diluent or excipient.

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid plugs, solidmicroparticulates, semi-solid and liquid (including multiple phases ordispersed systems) such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids, emulsions or powders; lozenges(including liquid-filled); chews; gels; fast dispersing dosage forms;films; ovules; sprays; and buccal/mucoadhesive patches.

Formulations suitable for oral administration may also be designed todeliver the compounds of formula (I) in an immediate release manner orin a rate-sustaining manner, wherein the release profile can be delayed,pulsed, controlled, sustained, or delayed and sustained or modified insuch a manner which optimises the therapeutic efficacy of the saidcompounds. Means to deliver compounds in a rate-sustaining manner areknown in the art and include slow release polymers that can beformulated with the said compounds to control their release.

Examples of rate-sustaining polymers include degradable andnon-degradable polymers that can be used to release the said compoundsby diffusion or a combination of diffusion and polymer erosion. Examplesof rate-sustaining polymers include hydroxypropyl methylcellulose,hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodiumcarboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone,xanthum gum, polymethacrylates, polyethylene oxide and polyethyleneglycol.

Liquid (including multiple phases and dispersed systems) formulationsinclude emulsions, suspensions, solutions, syrups and elixirs. Suchformulations may be presented as fillers in soft or hard capsules (made,for example, from gelatin or hydroxypropylmethylcellulose) and typicallycomprise a carrier, for example, water, ethanol, polyethylene glycol,propylene glycol, methylcellulose, or a suitable oil, and one or moreemulsifying agents and/or suspending agents. Liquid formulations mayalso be prepared by the reconstitution of a solid, for example, from asachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in Liang andChen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

The compounds of the invention may also be administered directly intothe blood stream, into subcutaneous tissue, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial and subcutaneous. Suitable devices forparenteral administration include needle (including microneedle)injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous or oily solutions. Wherethe solution is aqueous, excipients such as sugars (including butrestricted to glucose, manitol, sorbitol, etc.) salts, carbohydrates andbuffering agents (preferably to a pH of from 3 to 9), but, for someapplications, they may be more suitably formulated as a sterilenon-aqueous solution or as a dried form to be used in conjunction with asuitable vehicle such as sterile, pyrogen-free water.

Parenteral formulations may include implants derived from degradablepolymers such as polyesters (i.e., polylactic acid, polylactide,polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate),polyorthoesters and polyanhydrides. These formulations may beadministered via surgical incision into the subcutaneous tissue,muscular tissue or directly into specific organs.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation of co-solvents and/orsolubility-enhancing agents such as surfactants, micelle structures andcyclodextrins.

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler, as an aerosol spray froma pressurised container, pump, spray, atomiser (preferably an atomiserusing electrohydrodynamics to produce a fine mist), or nebuliser, withor without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or asnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound of formula (I), may conveniently be combined in the form of akit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

The compounds of the invention may be administered alone or incombination with one or more other compounds of the invention or incombination with one or more other drugs (or as any combinationthereof). The compounds of the present invention may be administered incombination with an oral contraceptive. Thus in a further aspect of theinvention, there is provided a pharmaceutical product containing anV_(1a) antagonist and an oral contraceptive as a combined preparationfor simultaneous, separate or sequential use in the treatment ofdysmenorrhoea.

The compounds of the present invention may be administered incombination with a PDE5 inhibitor. Thus in a further aspect of theinvention, there is provided a pharmaceutical product containing aV_(1a) antagonist and a PDEV inhibitor as a combined preparation forsimultaneous, separate or sequential use in the treatment ofdysmenorrhoea.

PDEV inhibitors useful for combining with V_(1a) antagonists include,but are not limited to:

-   -   (i)        5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7,4-pyrazolo[4,3-d]pyrimidin-7-one        (sildenafil, e.g. as sold as Viagra®) also known as        1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine        (see EP-A-0463756);        5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (see EP-A-0526004);        3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (see WO98/49166);        3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (see WO99/54333);        (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        also known as        3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (see WO99/54333);        5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        also known as        1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine        (see WO 01/271 13, Example 8);        5-[2-/so-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (see WO01/271 13, Example 15);        5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (see WO 01/271 13, Example 66);        5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-c(]pyrimidin-7-one        (see WO 01/271 12, Example 124);        5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-c(]pyrimidin-7-one        (see WO 01/27112, Example 132);        (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2′,1′:        6,1]pyrido[3,4-b]indole-1,4-dione (tadalafil, IC-351, Cialis®),        i.e. the compound of examples 78 and 95 of published        international application WO95/19978, as well as the compound of        examples 1, 3, 7 and 8;        2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one        (vardenafil, LEVITRA®) also known as        1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine,        i.e. the compound of examples 20, 19, 337 and 336 of published        international application WO99/24433; the compound of example 11        of published international application WO93/07124 (EISAI);        compounds 3 and 14 from Rotella D P, J. Med. Chem., 2000, 43,        1257; 4-(4˜ch!orobenzypamino-6,7,8-trimethoxyquinazoline;        N-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-yl)-4-propxyphenyl]sulfonyl]-1-methyl2-pyrrolidinepropanamide[“DA-8159”        (Example 68 of WO00/27848)]; and        7,8-dihydro-8-oxo-6-[2-propoxyphenyl]-1H-imidazo[4,5-g]quinazoline        and        1-[3-[1-[(4-fluorophenyl)methyl]-7,8-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl]-4-propoxyphenyl]carboxamide;        and    -   (ii)        4-bromo-5-(pyridyImethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone;        1-[4-[(1,3-benzodioxol-5-ylmethy)amiono]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylic        acid, monosodium salt;        (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one;        furazlocillin;        cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4-one;        3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;        3-acetyl-1-(2-chIorobenzyl)-2-propylindole-6-carboxylate;        4-bromo-5-(3-pyridyImethylamino)-6-(3-(4-chIorophenyl)propoxy)-3-(2H)pyridazinone;        1-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;        1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic        acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome);        Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa        Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering        Plough); GF-1 96960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai);        Bay-38-3045 & 38-9456 (Bayer); FR229934 and FR226807 (Fujisawa);        and Sch-51866.

The contents of the published patent applications and journal articlesand in particular the general formulae of the therapeutically activecompounds of the claims and exemplified compounds therein areincorporated herein in their entirety by reference thereto.

Conveniently, the PDEV inhibitor may be selected from sildenafil,tadalafil, vardenafil, DA-8159 and5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsuIphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.Most conveniently the PDE5 inhibitor is sildenafil and pharmaceuticallyacceptable salts thereof. Sildenafil citrate is a preferred salt.

The compounds of the present invention may be administered incombination with an NO donor.

Thus in a further aspect of the invention, there is provided apharmaceutical product containing a V_(1a) antagonist and a NO donor asa combined preparation for simultaneous, separate or sequential use inthe treatment of dysmenorrhoea.

The compounds of the present invention may be administered incombination with L-arginine, or as an arginate salt. Thus in a furtheraspect of the invention, there is provided a pharmaceutical productcontaining a V_(1a) antagonist and L-arginine as a combined preparationfor simultaneous, separate or sequential use in the treatment ofdysmenorrhoea.

The compounds of the present invention may be administered incombination with a COX inhibitor.

Thus in a further aspect of the invention, there is provided apharmaceutical product containing a V_(1a) antagonist and a COXinhibitor as a combined preparation for simultaneous, separate orsequential use in the treatment of dysmenorrhoea.

COX inhibitors useful for combining with the compounds of the presentinvention include, but are not limited to:

-   -   (i) ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen,        fenbufen, ketoprofen, indoprofen, pirprofen, carprofen,        oxaprozin, prapoprofen, miroprofen, tioxaprofen, suprofen,        alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid,        indomethacin, sulindac, tolmetin, zomepirac, diclofenac,        fenclofenec, alclofenac, ibufenac, isoxepac, furofenac,        tiopinac, zidometacin, acetyl salicylic acid, indometacin,        piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone,        mefenamic acid, tolfenamic acid, diflunisal, podophyllotoxin        derivatives, acemetacin, droxicam, floctafenine,        oxyphenbutazone, phenylbutazone, proglumetacin, acemetacin,        fentiazac, clidanac, oxipinac, mefenamic acid, meclofenamic        acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam,        etodolac, piprofen, salicylic acid, choline magnesium        trisalicylate, salicylate, benorylate, fentiazac, clopinac,        feprazone, isoxicam and        2-fluoro-a-methyl[1,1′-biphenyl]-4-acetic acid,        4-(nitrooxy)butyl ester (See Wenk, et al., Europ. J. Pharmacol.        453:319-324 (2002));    -   (ii) meloxicam, (CAS registry number 7 1125-38-7; described in        U.S. Pat. No. 4,233,299), or a pharmaceutically acceptable salt        or prodrug thereof;    -   (iii) celecoxib (U.S. Pat. No. 5,466,823), valdecoxib (U.S. Pat.        No. 5,633,272), deracoxib (U.S. Pat. No. 5,521,207), rofecoxib        (U.S. Pat. No. 5,474,995), etoricoxib (International Patent        Application Publication No. WO 98/03484), JTE-522 (Japanese        Patent Application Publication No. 9052882), or a        pharmaceutically acceptable salt or prodrug thereof;    -   (iv) Parecoxib (described in U.S. Pat. No. 5,932,598), which is        a therapeutically effective prodrug of the tricyclic Cox-2        selective inhibitor valdecoxib (described in U.S. Pat. No.        5,633,272), in particular sodium parecoxib;    -   (v) ABT-963 (described in International Patent Application        Publication No. WO 00/24719); and

(vi) Nimesulide (described in U.S. Pat. No. 3,840,597), flosulide(discussed in J. Carter. Exp. Opin. Ther. Patents. 8(1). 21-29 (1997)),NS-398 (disclosed in U.S. Pat. No. 4,885,367), SD 8381 (described inU.S. Pat. No. 6,034,256), BMS-347070 (described in U.S. Pat. No.6,180,651), S-2474 (described in European Patent Publication No. 595546)and MK-966 (described in U.S. Pat. No. 5,968,974).

The contents of any of the patent applications, and in particular thegeneral formulae of the therapeutically active compounds of the claimsand exemplified compounds therein, are incorporated herein in theirentirety by reference thereto.

If a combination of active agents is administered, then they may beadministered simultaneously, separately or sequentially.

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 0.01 mg and 1000mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg depending,of course, on the mode of administration. The total daily dose may beadministered in single or divided doses and may, at the physician'sdiscretion, fall outside of the typical range given herein. Thesedosages are based on an average human subject having a weight of about60 kg to 70 kg. The physician will readily be able to determine dosesfor subjects whose weight falls outside this range, such as infants andthe elderly.

Synthetic Methods

The compounds of the present invention can be prepared according to theprocedures of the specific examples provided herein below. Moreover, byutilising the procedures described herein, one of ordinary skill in theart can readily prepare additional compounds that fall within the scopeof the present invention claimed herein. The compounds illustrated inthe examples are not, however, to be construed as forming the only genusthat is considered as the invention. The examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds.

The compounds of the invention may be isolated in the form of theirpharmaceutically acceptable salts, such as those described previouslyherein above.

It may be necessary to protect reactive functional groups (e.g. hydroxy,amino, thio or carboxy) in intermediates used in the preparation ofcompounds of the invention to avoid their unwanted participation in areaction leading to the formation of the compounds. Conventionalprotecting groups, for example those described by T. W. Greene and P. G.M. Wuts in “Protective groups in organic chemistry” John Wiley and Sons,4^(th) Edition, 2006, may be used. For example, a common aminoprotecting group suitable for use herein is tert-butoxy carbonyl (Boc),which is readily removed by treatment with an acid such astrifluoroacetic acid or hydrogen chloride in an organic solvent such asdichloromethane. Alternatively the amino protecting group may be abenzyloxycarbonyl (Z) group which can be removed by hydrogenation with apalladium catalyst under a hydrogen atmosphere or9-fluorenylmethyloxycarbonyl (Fmoc) group which can be removed bysolutions of secondary organic amines such as diethylamine or piperidinein an organic solvents. Carboxyl groups are typically protected asesters such as methyl, ethyl, benzyl or tert-butyl which can all beremoved by hydrolysis in the presence of bases such as lithium or sodiumhydroxide. Benzyl protecting groups can also be removed by hydrogenationwith a palladium catalyst under a hydrogen atmosphere whilst tert-butylgroups can also be removed by trifluoroacetic acid. Alternatively atrichloroethyl ester protecting group is removed with zinc in aceticacid. A common hydroxy protecting group suitable for use herein is amethyl ether, deprotection conditions comprise refluxing in 48% aqueousHBr for 1-24 hours, or by stirring with borane tribromide indichloromethane for 1-24 hours. Alternatively where a hydroxy group isprotected as a benzyl ether, deprotection conditions comprisehydrogenation with a palladium catalyst under a hydrogen atmosphere.

Experimental

The invention is illustrated by the following non-limiting examples inwhich the following abbreviations and definitions are used:

DCM Dichloromethane DMF N,N-Dimethylformamide EtOAc Ethyl Acetate hHours LCMS Liquid chromatography mass spectrometry Me Methyl MeCNAcetonitrile MeOH Methanol Min Minutes MS Mass spectrum NMR Nuclearmagnetic resonance spectrum - NMR spectra were recorded at a frequencyof 270 or 400 MHz unless otherwise indicated Pet. Ether Petroleum etherfraction boiling at 60-80° C. RT Room temperature THF Tetrahydrofuran

All reactions were carried out under an atmosphere of nitrogen unlessspecified otherwise.

¹H NMR spectra were recorded on a Jeol EX 270 (270 MHz) or BruckerAvarice III (400 MHz) spectrometer with reference to deuterium solvent(CDCl₃ unless otherwise stated) and at RT. Molecular ions were obtainedusing LCMS which was carried out using a Chromolith Speedrod RP-18ecolumn, 50×4.6 mm, with a linear gradient 10% to 90% 0.1% HCO₂H/MeCNinto 0.1% HCO₂H/H₂O over 11 min, flow rate 1.5 mL/min. Data wascollected using a Thermofinnigan Surveyor MSQ mass spectrometer withelectospray ionisation in conjunction with a Thermofinnigan Surveyor LCsystem.

Chemical names were generated using the Autonom software provided aspart of the ISIS draw package from MDL Information Systems.

Where products were purified by flash chromatography, ‘silica’ refers tosilica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g.Merck silica gel 60), and an applied pressure of nitrogen up to 10 p.s.iaccelerated column elution. Reverse phase preparative HPLC purificationswere carried out using a Waters 2525 binary gradient pumping system atflow rates of typically 20 ml/min using a Waters 2996 photodiode arraydetector.

All solvents and commercial reagents were used as received.

Synthesis of Intermediate Compounds Method A Compound1:1-Pyrimidin-2-yl-piperidine-4-carboxylic acid ethyl ester

A mixture of 2-chloropyrimidine (2.28 g, 20 mmol) and ethylisonipecotate (4.72 g, 30 mmol) in toluene (10 ml) was heated at refluxfor 18 h. then cooled to RT. The mixture was diluted with EtOAc andwashed with saturated aqueous NaHCO₃. The organics were separated,dried, and the solvents removed in vacuo. The residue was purified byflash chromatography on silica (eluant: EtOAc/pet. ether 40/60 v/v) toyield the title compound as a colourless oil.

Yield=4.00 g, 81%. (ESI⁺): [M+H]⁺=236.0

Method B Compound 2: 1-(2-Fluorophenyl)-piperidine-4-carboxylic acidethyl ester

To a mixture of 1-bromo-2-fluorobenzene (5 g, 28.6 mmol) and ethylisonipecotate (13.2 ml, 85.3 mmol [3 eq.]) in toluene (100 ml) wereadded sodium tert-butoxide (3.43 g, 35.7 mmol [1.25 eq.]),tris(dibenzylideneacetone)dipalladium (262 mg, 0.29 mmol [0.01 eq.]) andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (534 mg, 0.86 mmol [0.03eq.]), and the mixture was heated at 120° C. for 16 h. then cooled toRT. Water (100 ml) was added, and the layers separated. The organicswere separated, dried, and the solvents removed in vacuo. The residuewas purified by flash chromatography on silica (eluant: EtOAc/pet. ether15/85 v/v) to yield the title compound as a yellow oil.

Yield=3.60 g=50.1%. (ESI⁺): [M+H]⁺=252.2

The following compounds were prepared using analogous methods to theabove:

(ESI⁺): Compound Method R⁷ R⁸ [M + H]⁺ 3 A CF₃ H 304.1 4 A H

264.1

(ESI⁺): Compound Method R⁶ R⁷ R⁸ [M + H]⁺  5 A H H H 235.1  6 B Me H H249.4  7 A H Me H 249.2  8 B H H Me 249.4  9 B OMe H H 265.2 10 A H OMeH 265.0 11 B H H Ome 265.4 12 B H H CF3 303.4 13 B H H CN 260.2

Compound Method R⁷ (ESI⁺): [M + H]⁺ 14 A Me 249.5 15 B OMe 265.4

(ESI⁺): Compound Method R⁶ R⁷ R⁸ [M + H]⁺ 16 B Me H H 249.2 17 B H Me H249.2 18 B H H Me 249.2

Compound Method R⁶ (ESI⁺): [M + H]⁺ 19 B Me 249.2

Compound Method (ESI⁺): [M + H]⁺ 20 A 236.2

Com- (ESI⁺): pound Method R⁶ R⁷ R⁸ [M + H]⁺ 21 B H H H 234.2 22 B F H H252.2 23 B H F H 252.2 24 B H H F 252.2 25 B Cl H H 268.2 26 B H H Cl268.2 27 B Me H H 248.2 28 B H Me H 248.1 29 B H H Me 248.1 30 B OMe H H264.2 31 B H OMe H 264.2 32 B H H OMe 264.2 33 B H H

262.1 34 B H H

276.1 35 B H H

276.1 36 B H

H 310.0 37 B H H CF₃ 302.2 38 A CN H H 259.2 39 B H CN H 259.2 40 A H HCN 259.2 41 A NO₂ H H 279.2 42 B H NO₂ H 279.2 43 A H H NO₂ 279.2

Compound 44: 1-Pyrimidin-2-yl-piperidine-4-carboxylic acid

A mixture of 1-pyrimidin-2-yl-piperidine-4-carboxylic acid ethyl ester(4.00 g, 17.00 mmol) and lithium hydroxide monohydrate (1.73 g, 34.00mmol) in THF (50 ml)/water (30 ml) at RT was stirred for 18 h, then thesolvents were removed in vacuo. The residue was purified by flashchromatography on silica (eluant: chloroform/MeOH/acetic acid 50/2/1v/v/v) to yield the title compound as a white solid.

Yield=3.00 g, 85.2%

(ESI⁺): [M+H]⁺=208.2

The following compounds were prepared using analogous methods to theabove:

Compound R⁷ R⁸ (ESI⁺): [M + H]⁺ 45 CF₃ H 276.1 46 H

236.1

(ESI⁺): Compound R⁶ R⁷ R⁸ [M + H]⁺ 47 H H H 207.2 48 Me H H 221.4 49 HMe H 221.1 50 H H Me 221.3 51 OMe H H 237.2 52 H OMe H 237.1 53 H H OMe237.4 54 H H CF3 275.3 55 H H CN 232.1

Compound R⁷ (ESI⁺): [M + H]⁺ 56 Me 221.1 57 OMe 237.4

(ESI⁺) Compound R⁶ R⁷ R⁸ [M + H]⁺ 58 H H H 207.1 59 Me H H 221.2 60 H MeH 221.4 61 H H Me 221.2

Compound R⁶ (ESI⁺): [M + H]⁺ 62 Me 221.2

Compound (ESI⁺): [M + H]⁺ 63 208.2

Compound R⁶ R⁷ R⁸ [M + H]⁺ 64 H H H 206.1 65 F H H 224.2 66 H F H 224.267 H H F 224.2 68 Cl H H 240.1 69 H H Cl 240.1 70 Me H H 220.2 71 H Me H220.0 72 H H Me 220.0 73 OMe H H 236.0 74 H OMe H 236.2 75 H H OMe 236.276 H H

234.1 77 H H

248.1 78 H H

248.1 79 H

H 282.2 80 H H CF₃ 274.2 81 CN H H 231.0 82 H CN H 231.2 83 H H CN 231.284 NO₂ H H 251.1 85 H NO₂ H 251.2 86 H H NO₂ 251.1

The following were prepared using methods analogous to those describedin Example E5 (p. 32) of WO2006021213.

(ESI⁺): Compound R¹ R² [M + H]⁺ 87 H Me 88 H

271.4 89 F

289.4 90 Me

228.1 91 Me

242.4 92 Me

240.4 93 Me

256.4 94 Me

256.4 95 Me

298.4 96 Me

285.5 97 Me

284.4 98 Me

269.2 99 Cl Me 234.1 100 Cl

248.4 101 Cl

262.2, 264.2 102 Cl

260.1 103 Cl

302.0, 304.0 104 Cl

303.2 105 Cl

318.4 106 Cl

296.1, 298.1 107 Cl

314.1 108 Cl

314.1 109 Cl

309.9, 312.0 110 Cl

305.4

The following were prepared using methods analogous to those describedin Example E1 (p. 23) of WO2006021213.

(ESI⁺): Compound R³ R⁴ [M + H]⁺ 111 H Me 201.3 112 H

269.2 113 F Me 219.0 114 F

233.1 115 F

261.2 116 Me Me 216.1 117 Me

291.2 118 Cl Me 235.2, 237.2 119 Cl

247.2, 249.2 120 Cl

297.1, 299.1

The following compounds were prepared using methods analogous topublished procedures in J. Med. Chem. 1980, p. 462.

(ESI⁺): Compound R⁵ [M + H]⁺ 121 H 185.0 122 F 203.2 123 Me 199.3

SYNTHESIS OF EXAMPLES

The following examples were prepared to illustrate the invention:

Example 1(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone

To a suspension of5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (200mg, 0.9 mmol) in DCM (5 ml) were added oxalyl chloride (0.10 ml, 1.18mmol) and DMF (3 drops) and the mixture was stirred for 2 h. Thereaction mixture was concentrated in vacuo, azeotroped with toluene (×2)and DCM (×2). The residue was redissolved in DCM (5 ml) and added to asolution of9-methyl-2-morpholin-4-yl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene(129 mg, 0.45 mmol) in pyridine (5 ml) at 80° C. The reaction was heatedat 80° C. for 18 h and then allowed to cool to RT. The mixture wasdiluted with DCM (50 ml) and washed with sat. aq. NaHCO₃ (20 ml). Theorganics were dried, and the solvents removed in vacuo. The residue waspurified by flash chromatography on silica (eluant: chloroform/MeOH100/3 v/v) and the residue to yield a brown oil, which solidified whentreated with MeCN (2 ml). The MeCN was removed in vacuo, and theresulting brown solid was triturated with diethyl ether and filtered toyield the title compound as a light brown solid (87 mg, 39.4%).

1H NMR (DMSO-d₆): 0.92 (1H, d, J=11.3 Hz), 1.09-1.18 (1H, m), 1.61-1.70(1H, m), 1.71-1.75 (1H, m), 2.09 (3H, s), 2.25-2.33 (1H, m), 2.34 (3H,s), 2.52-2.63 (1H, m), 2.64-2.70 (3H, m), 2.96-3.09 (1H, m), 3.21-3.24(4H, m), 3.69 (4H, t, J=4.9 Hz), 3.93 (1H, d, J=13.1 Hz), 4.20 (1H, d,J=13.1 Hz), 4.52 (1H, d, J=10.3 Hz), 6.64 (1H, d, J=8.7 Hz), 6.98 (1H,dd, J=0.9, 7.8 Hz), 7.17 (1H, d, J=7.0 Hz), 7.28 (1H, dd, J=2.3, 8.7Hz), 7.86 (2H, d, J=2.3 Hz), 11.10 (1H, s)

(ESI⁺): [M+H]⁺=487.61

Example 2(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone

To a suspension of3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (116mg, 0.53 mmol) in DCM (5 ml) were added oxalyl chloride (0.06 ml, 0.69mmol) and DMF (2 drops) and the mixture was stirred for 1 h. Thereaction mixture was concentrated in vacuo, azeotroped with toluene (×2)and DCM (×2). The residue was redissolved in DCM (3 ml) and added to asolution of(9-methyl-2-morpholin-4-yl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene(150 mg, 0.53 mmol) in DCM (2 ml) and triethylamine (0.148 ml, 1.05mmol) at 0° C. The reaction was stirred at RT for 3 days. Solvents wereremoved in vacuo. The residue was purified by flash chromatography onsilica (eluant: DCM/MeOH 98/2 to 95/5 v/v). The product wasrecrystallised from EtOAc/petroleum ether to give the title compound asan orange solid (85 mg, 33%).

¹H NMR (DMSO-d₆) δ 0.97-1.02 (1H, m), 1.30-1.39 (1H, m), 1.79-1.87 (2H,m), 2.14 (3H, s), 2.12-2.22 (1H, m), 2.34 (3H, s), 2.47-2.73 (4H, m),3.04-3.14 (2H, m), 3.23-3.38 (5H, m), 3.69 (4H, t, J=4.5 Hz), 4.54-4.60(1H, m), 6.84 (1H, dd, J=4.8, 7.2 Hz), 6.98 (1H, d, J=7.8 Hz), 7.18 (1H,d, J=7.8 Hz), 7.42 (1H, d, J=7.0 Hz), 7.86 (1H, s), 8.00 (1H, dd, J=1.5,4.8 Hz), 11.11 (1H, s).

(ESI⁺): [M+H]⁺=487.2

Example 3(3′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone

To a suspension of3′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(415 mg, 1.75 mmol) in DCM (5 ml) were added oxalyl chloride (0.20 ml,2.29 mmol) and DMF (3 drops) and the mixture was stirred for 2 h. Thereaction mixture was concentrated in vacuo, azeotroped with toluene (×2)and DCM (×2). The residue was redissolved in DCM (5 ml) and added to asolution of9-methyl-2-morpholin-4-yl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene(129 mg, 0.45 mmol) in DCM (3 ml) and triethylamine (0.43 ml, 3.08mmol). The reaction was stirred at RT for 72 h and the solvents removedin vacuo. The residue was purified by flash chromatography on silica(eluant: DCM/MeOH 100/2 to 100/5 v/v) and the residue was purified byprep. HPLC.

The relevant fractions were collected and the solvents removed in vacuo.The residue was partitioned between DCM and sat. aq. NaHCO₃. Theorganics were separated, dried and the solvents were removed in vacuo.The residue was lypophilised from MeCN/water to yield the title compoundas a yellow solid (87 mg, 20%).

¹H NMR (DMSO-d₆): δ 0.94 (1H, d, J=12.1 Hz), 1.25-1.35 (1H, m),1.73-1.86 (2H, m), 2.19 (1H, t, J=12.7 Hz), 2.34 (3H, s), 2.46-2.53 (1H,m), 2.57-2.71 (3H, m), 3.01-3.09 (1H, m), 3.25 (4H, brs), 3.63 (1H, d,J=12.5 Hz), 3.69 (4H, t, J=4.7 Hz), 3.73 (3H, s), 3.89 (1H, d, J=12.5Hz), 4.55 (1H, d, J=8.0 Hz), 6.80 (1H, dd, J=4.7, 8.0 Hz), 6.97 (1H, dd,J=1.2, 8.0 Hz), 7.15 (1H, dd, J=1.2, 8.0 Hz), 7.16-7.18 (1H, m), 7.69(1H, dd, J=1.2, 4.7 Hz), 7.85 (1H, brs), 11.13 (1H, brs).

(ESI⁺): [M+H]⁺=503.2

Example 4(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone

To a suspension of6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-carboxylic acid (mg,1.76 mmol) in DCM (5 ml) were added oxalyl chloride (0.20 ml, 2.29 mmol)and DMF (2 drops) and the mixture was stirred for 2 h. The reactionmixture was concentrated in vacuo, azeotroped with toluene (×2) and DCM(×2). The residue was redissolved in DCM (5 ml) and added to a solutionof9-methyl-2-morpholin-4-yl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene(250 mg, 0.88 mmol) in DCM (3 ml) and triethylamine (0.43 ml, 3.08 mmol)at 0° C. The reaction was then stirred at RT for 24 h and the solventsremoved in vacuo. The residue was purified by flash chromatography onsilica (eluant: DCM/MeOH 100/2 to 100/5 v/v) and the residue waspurified by prep. HPLC. The relevant fractions were collected and thesolvents removed in vacuo. The residue was partitioned betweenchloroform and sat. aq. NaHCO₃. The organics were separated, dried andthe solvents were removed in vacuo. The residue was lypophilised fromMeCN/water to yield the title compound as an off-white solid (77 mg,18%).

¹H NMR (DMSO-d₆) δ1.03-1.07 (1H, m), 1.28-1.38 (1H, m), 1.84-1.89 (2H,m), 2.21-2.28 (1H, m), 2.37 (3H, s), 2.41 (3H, s), 2.62-2.78 (4H, m),3.09-3.18 (1H, m), 3.34 (4H, s), 3.48 (1H, d, J=12.5 Hz), 3.73 (1H, d,J=12.7 Hz), 3.76-3.78 (4H, m), 4.59-4.64 (1H, m), 7.04-7.08 (2H, m),7.21 (1H, dd, J=2.9, 8.5 Hz), 7.27 (1H, d, J=7.9 Hz), 7.88 (1H, s), 8.10(1H, d, J=2.9 Hz), 11.22 (1H, s).

(ESI⁺): [M+H]⁺=487.26

Example 5(9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone

To a suspension of6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (306mg, 1.39 mmol) in DCM (5 ml) were added oxalyl chloride (0.16 ml, 1.80mmol) and DMF (2 drops) and the mixture was stirred for 1 h. Thereaction mixture was concentrated in vacuo, azeotroped with toluene (×2)and DCM (×2). The residue was redissolved in DCM (3 ml) and added to asolution of9-fluoro-2-morpholin-4-yl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene(200 mg, 0.69 mmol) in DCM (2 ml) and triethylamine (0.341 ml, 2.43mmol) at 0° C. The reaction was stirred at RT for 3 h. Saturated NaHCO₃solution was added and the layers were partitioned. The organic layerwas washed with brine, dried, and the solvents were removed in vacuo.The residue was purified by flash chromatography on silica (eluant:DCM/MeOH 100/2 to 100/5 v/v). The residue was further purified furtherby flash chromatography on silica (eluant: DCM/MeOH 96/4tv/v) thenlypophilised from MeCN/water to give the title compound as an off-whitepowder (64 mg, 19%).

¹H NMR (DMSO-d₆): δ 0.92 (1H, d, J=11.7 Hz), 1.05-1.15 (1H, m),1.59-1.70 (1H, m), 1.77 (1H, d, J=11.7 Hz), 2.24 (3H, s), 2.33 (1H, dt,J=2.6, 12.0 Hz), 2.57-2.74 (4H, m), 3.01-3.11 (1H, m), 3.25 (2H, t,J=4.6 Hz), 3.30-3.35 (2H, m), 3.70 (4H, t, J=4.6 Hz), 4.01 (1H, d,J=13.1 Hz), 4.28 (1H, d, J=13.1 Hz), 4.55 (1H, dd, J=5.2, 12.5 Hz), 6.41(1H, d, J=7.3 Hz), 6.50 (1H, d, J=8.3 Hz), 6.98 (1H, dt, J=2.6, 7.8 Hz),7.30-7.41 (2H, m), 7.72 (1H, dd, J=3.6, 10.4 Hz), 11.23 (1H, s).

(ESI⁺): [M+H]⁺=491.5

The following examples were prepared using methods analogous to theabove:

TABLE 1

(ESI⁺): Example R¹ [M + H]⁺ 6 H 389.2 7 Cl 423.3

TABLE 2

Ex- (ESI⁺): ample R¹ R² R⁶ R⁷ R⁸ [M + H]⁺ 8 H Me H H H 388.3 9 H

H H H 459.2 10 H

Me H H 473.5 11 H

H Me H 473.2 12 H

H H Me 473.3 13 F

H H H 477.6 14 F

Me H H 491.5 15 F

H Me H 491.5 16 F

H H Me 491.6 17 Me

Me H H 430.2 18 Me

H Me H 430.2 19 Me

H Me H 430.2 20 Me

H H H 430.2 21 Me

Me H H 444.3 22 Me

H Me H 444.3 23 Me

H H Me 444.5 24 Me

H H H 428.2 25 Me

H H Me 442.2 26 Me

H H H 444.2 27 Me

H H Me 458.3 28 Me

H H H 444.2 29 Me

H H Me 458.3 30 Me

H H Me 500.3 31 Me

H H H 473.6 32 Me

H Me H 487.2 33 Me

H OMe H 503.2 34 Me

H H OMe 503.2 35 Me

H H CF₃ 541.5 36 Me

H H CN 498.2 37 Me

Me H H 486.3 38 Me

H Me H 486.3 39 Me

H H Me 486.3 40 Me

OMe H H 502.2 41 Me

H OMe H 502.2 42 Me

H H OMe 502.2 43 Me

H H Me 471.3 44 Cl Me H H H 422.1 45 Cl Me H H Me 458.7 46 Cl

H H H 436.1 47 Cl

H H H 450.0, 452.1 48 Cl

H H H 448.0 49 Cl

H H H 490.1, 492.1 50 Cl

H H H 491.1, 493.1 51 Cl

H H H 506.2, 508.2 52 Cl

H H Me 520.5, 522.5 53 Cl

H H H 484.1, 486.1 54 Cl

H H H 502.2 55 Cl

H H H 502.2 56 Cl

H H H 498.1, 500.1 57 Cl

H H H 493.1, 495.1 58 Cl

H Me H 507.2, 509.2 59 Cl

H H Me 507.2, 509.2

TABLE 3

(ESI⁺) Example R¹ R² R⁷ [M + H]⁺ 60 H

Me 473.21 61 Me

Me 430.23 62 Me

Me 444.24 63 Me

Me 487.23 64 Me

OMe 503.21 65 Me

Me 486.25 66 Me

OMe 502.3  67 Cl

Me 507.2, 509.2 68 Cl

OMe 523.19

TABLE 4

(ESI⁺) Example R¹ R² R⁶ R⁷ R⁸ [M + H]⁺ 69 Me

Me H H 487.26 70 Me

H Me H 487.5 

TABLE 5

(ESI⁺) Example R¹ R² R⁶ [M + H]⁺ 71 Me

Me 487.28

TABLE 6

(ESI⁺) Example R² [M + H]⁺ 72 Me 420.9  73

435.2/437.2 74

449.0/451.1 75

447.0/449.1 76

489.3/491.3 77

490.1/492.1 78

505.1/507.1 79

483.1/485.1 80

501.22 81

501.21 82

497.1/499.1

TABLE 7

(ESI⁺) Example R⁶ R⁷ R⁸ [M + H]⁺ 83 F H H 439.2, 441.2 84 H F H 439.2,441.2 85 H H F 439.2, 441.3 86 Cl H H 455.0, 457.0 87 H Cl H 455.0,457.0 88 H H Cl 455.2, 457.2 89 Me H H 435.0, 437.1 90 H Me H 435.0,437.1 91 H H Me 435.0, 437.0 92 OMe H H 451.2, 453.2 93 H OMe H 451.1,453.2 94 H H OMe 451.2, 453.3 95 H H

449.25 96 H H

463.16 97 H H

463.16

TABLE 8

(ESI⁺) Example R³ R⁴ R⁷ R⁸ [M + H]⁺  98 H Me H H 390.2  99 H

CF₃ H 526.1 100 F Me H H 408.2 101 F Me CF₃ H 490.2 102 Me Me H H 404.2103 Cl Me H H 426.2 104 Cl

H H 486.2 105 Cl

H

514.2, 516.2

TABLE 9

(ESI⁺) Example R³ R⁴ R⁶ R⁷ R⁸ [M + H]⁺ 106 H Me H H H 389.1 107 F

H H Me 435.2 108 F

H H Me 463.2 109 Me Me H H H 403.2 110 Me Me Me H H 417.1 111 Me Me H MeH 417.2 112 Me Me H H Me 417.1 113 Me Me OMe H H 433.1 114 Me

H H Me 493.3 115 Cl Me H H H 423.1, 425.1 116 Cl Me Me H H 437.2, 439.2117 Cl Me H Me H 437.2 118 Cl Me H H Me 437.2, 439.2 119 Cl Me OMe H H453.2 120 Cl

Me H H 451.1 121 Cl

H Me H 451.1 122 Cl

H H Me 451.2, 453.2 123 Cl

H H Me 499.1, 501.1

TABLE 10

(ESI⁺) Example R³ R⁴ R⁷ [M + H]⁺ 124 Me Me Me 417.2 125 Cl Me Me 437.2126 Cl

Me 451.1

TABLE 11

(ESI⁺) Example R³ R⁴ R⁶ R⁷ R⁸ [M + H]⁺ 127 Me Me F H H 420.25 128 Me MeH Me H 416.2  129 Me Me H H Me 416.27 130 Me Me H OMe H 432.2  131 Me MeH H OMe 432.2  132 Me Me H H

430.2  133 Me Me H H CF₃ 470.2  134 Cl Me F H H 440.2  135 Cl Me H Me H436.2, 438.2 136 Cl Me H H Me 436.22 137 Cl Me H OMe H 452.2, 454.2 138Cl Me H H OMe 452.1, 454.1 139 Cl Me H H

450.2, 452.2 140 Cl Me H H CF₃ 490.2 

TABLE 12

(ESI⁺) Example R³ R⁴ R⁸ [M + H]⁺ 141 Me Me Me 417.2 142 Cl Me Me 437.2,439.2

TABLE 13

(ESI⁺) Examples R⁵ Ar [M + H]⁺ 143 H

374.2 144 H

(373.2 145 H

387.3 146 H

373.1 147 H

373.2 148 H

374.0 149 H

372.1 150 F

391.1 151 F

390.2 152 Me

387.2 153 Me

386.0

TABLE 14

(ESI⁺) Example R⁶ R⁷ R⁸ [M + H]⁺ 154 F H H 390.0 155 H F H 390.2 156 H HF 390.2 157 Cl H H 406.0, 408.1 158 H H Cl 406.2, 408.2 159 Me H H 386.2160 H Me H 386.3 161 H H Me 386.2 162 OMe H H 402.3 163 H OMe H 402.3164 H H OMe 402.3 165 H H

400.2 166 H H

414.3 167 H H

414.3 168 H

H 448.3 169 H H CF₃ 440.2 170 H CN H 397.2 171 H H CN 397.3 172 NO₂ H H401.2 173 H NO₂ H 417.2 174 H H NO₂ 417.2

Example 175[1-(2-Amino-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone

[1-(2-nitro-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone(1.0 g, 2.4 mmol) and 10% Pd/C (100 mg) were stirred in ethanol (20 ml)and DMF (5 ml) under an atmosphere of H₂ for 3 h. The mixture wasfiltered through Celite™ and solvent removed in vacuo. The residue waspurified by flash chromatography on silica (eluant: EtOAc/petroleumether 40/60 v/v) to yield the title compound (814 mg, 2.1 mmol, 88%) asa pale orange solid.

¹H NMR δ 1.89-2.03 (4H, m), 2.36-2.43 (3H, m), 3.02-3.16 (2H, m), 3.95(2H, brs), 4.10-4.18 (1H, m), 4.71 (1H, d, J=13.8 Hz), 5.27 (1H, d,J=13.8 Hz), 5.98-6.06 (3H, m), 6.58-6.70 (4H, m), 6.82-6.88 (2H, m),7.25-7.44 (3H, m).

(ESP⁺): [M+H]⁺=387.25

The following example was prepared by methods analogous to the above:

TABLE 15

(ESI⁺) Example R⁶ R⁷ R⁸ [M + H]⁺ 176 H H NH₂ 387.3

Example 177[1-(2-Aminomethyl-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone

Cobalt (II) chloride hexahydrate (240 mg, 1.00 mmol) was added to asolution of2-[4-(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-piperidin-1-yl]-benzonitrile(200 mg, 0.50 mmol) in MeOH (10 mL) at RT, and the mixture was stirredfor 10 min before being cooled to 0° C. Sodium borohydride (191 mg, 0.5mmol) was added portionwise, and the mixture was then stirred at 0° C.for 15 min and at RT for a further 48 h. before being purified by flashchromatography on silica (eluant: with DCM/MeOH/25% aq. ammonia 90/10/2v/v/v) to yield the title compound (140 mg, 0.30 mmol, 69%) as a whitesolid.

¹H NMR δ 1.48-1.52 (1H, m), 1.89-1.99 (3H, m), 2.36-2.49 (3H, m),2.98-3.11 (4H, m), 3.93 (2H, s), 4.13 (1H, d, J=16.1 Hz), 4.69 (1H, d,J=13.6 Hz), 5.26 (1H, d, J=13.6 Hz), 5.93-5.97 (2H, m), 6.05 (1H, t,J=3.0 Hz), 6.57 (1H, s), 7.04-7.43 (8H, m).

(ESI⁺): [M+H]⁺=401.2

The following example was prepared by methods analogous to the above:

TABLE 16

(ESI⁺) Example R⁶ R⁷ R⁸ [M + H]⁺ 178 H H CH₂NH₂ 401.2

TABLE 17 NMR Data for Examples Example ¹H NMR 6 1.05-1.17 (1H, m),1.17-1.42 (1H, m), 1.75-2.00 (2H, m), 2.30-2.50 (1H, m), 2.42 (3H, s),2.60-2.82 (3H, m), 2.82-3.00 (1H, m), 3.22-3.42 (1H, m), 4.46 (1H, d, J= 13.4 Hz), 4.65-4.82 (2H, m), 6.38 (1H, t, J = 4.7 Hz), 7.12-7.28 (2H,m), 7.30-7.44 (1H, m) 8.15-(1H, d, J = 7.4 Hz), 8.20 (1H, d, J = 4.7 Hz)7 1.04-1.16 (1H, m), 1.23-1.40 (1H, m), 1.71-2.00 (2H, m), 2.44 (3H, s),2.45-2.53 (1H, m), 2.66-2.98 (4H, m), 3.22-3.41 (1H, m), 4.47 (1H, d, J= 13.4 Hz), 4.68-4.82 (2H, m), 6.39 (1H, t, J = 4.7 Hz), 7.07-7.22 (2H,m), 8.20-8.25 (3H, m), 9.29 (1H, s) 8 1.02-1.13 (1H, m), 1.21-1.43 (1H,m), 1.77-2.02 (2H, m), 2.30-2.32 (1H, m), 2.39 (3H, s), 2.54-2.79 (3H,m), 2.80-2.97 (1H, m), 3.21-3.40 (1H, m), 3.88-4.00 (1H, m) 4.21-4.35(1H, m), 4.70 (1H, dd, J = 5.2 Hz) 6.48-6.53 (2H, m), 7.18-7.20 (2H, m),7.30-7.41 (2H, m), 8.07 (1H, d, J = 3.9 Hz), 8.19 (1H, s), 10.40 (1H, s)9 (DMSO-d6) 0.92-0.95 (1H, m), 1.08-1.18 (1H, m), 1.62-1.79 (2H, m),2.28-2.35 (1H, m), 2.59-2.74 (4H, m), 3.02-3.10 (1H, m), 3.27-3.31 (4H,m), 3.69-3.72 (4H, m), 4.01 (1H, d, J = 13.4 Hz), 4.28 (1H, d, J = 13.2Hz), 4.54-4.58 (1H, m), 6.51-6.59 (1H, m), 6.72 (1H, d, J = 8.6 Hz),7.18-7.21 (1H, m), 7.34 (2H, d, J = 6.7 Hz), 7.42-7.46 (1H, m),7.98-8.07 (2H, m), 11.17 (1H, s). 10 (DMSO-d6): 0.99 (1H, d, J = 12.2Hz), 1.29-1.41 (1H, m), 1.79-1.90 (2H, m), 2.14 (3H, s), 2.14-2.23 (1H,m), 2.47-2.75 (4H, m), 3.04-3.14 (2H, m), 3.23-3.38 (5H, m), 3.70 (4H,t, J = 4.7 Hz), 4.59 (1H, d, J = 10.9 Hz), 6.84 (1H, dd, J = 4.7, 7.5Hz), 7.16-7.20 (1H, m), 7.31-7.36 (2H, m), 7.42 (1H, dd, =1.4, 7.5 Hz),8.00 (1H, dd, J = 1.8, 4.7 Hz), 8.06 (1H, brs), 11.15 (1H, brs). 11(DMSO-d6) 0.92-0.95 (1H, m), 1.08-1.18 (1H, m), 1.61-1.72 (1H, m),1.76-1.79 (1H, m), 2.16 (3H, s), 2.30-2.35 (1H, m), 2.61-2.76 (4H, m),3.01-3.10 (1H, m), 3.31-3.36 (4H, m), 3.71-3.73 (4H, m), 4.02 (1H, d, J= 13.2 Hz), 4.26 (1H, d, J = 13.3 Hz), 4.54-4.59 (1H, m), 6.42 (1H, d, J= 5.1 Hz), 6.59 (1H, s), 7.27-7.40 (3H, m), 7.88 (1H, d, J = 5.1 Hz),7.94-8.01 (1H, m). 12 (DMSO-d6) 0.97-1.06 (1H, m), 1.15-1.25 (1H, m),1.69-1.84 (2H, m), 2.16 (3H, s), 2.30-2.37 (1H, m), 2.60-2.68 (1H, m),2.70-2.82 (3H, m), 3.07-3.16 (1H, m), 3.34-3.38 (4H, m), 3.76-3.79 (4H,m), 4.01 (1H, d, J = 13.3 Hz), 4.27 (1H, d, J = 12.9 Hz), 4.60-4.65 (1H,m), 6.72 (1H, d, J = 8.7 Hz), 7.24-7.28 (1H, m), 7.35-7.43 (3H, m), 7.94(1H, d, J = 1.8 Hz), 7.99-8.06 (1H, m), 11.26 (1H, d, J = 5.3 Hz). 13(DMSO-d6): d 0.92 (1H, d, J = 12.2 Hz), 1.10-1.16 (1H, m), 1.60-1.71(1H, m), 1.77 (1H, d, J = 12.2 Hz), 2.33-2.40 (1H, m), 2.61-2.76 (4H,m), 3.01-3.13 (1H, m), 3.31-3.34 (4H, m), 3.69 (4H, t, J = 4.4 Hz), 4.00(1H, d, J = 12.7 Hz), 4.28 (1H, d, J = 12.7 Hz), 4.51-4.57 (1H, m), 6.54(1H, dd, J = −5.2, 7.1 Hz), 6.72 (1H, d, J = 8.7 Hz), 6.99 (1H, dt, J =2.9, 8.2 Hz), 7.36-7.40 (1H, m), 7.41-7.46 (1H, m), 7.68-7.76 (1H, m),8.03 (1H, dd, J = 1.2, 4.9 Hz), 11.24 (1H, s) 14 (DMSO-d6): 0.98 (1H, d,J = 10.9 Hz), 1.28-1.38 (1H, m), 1.81-1.91 (2H, m), 2.14 (3H, s), 2.21(1H, dt, J = 1.9, 12.2 Hz), 2.54 (2H, dd, J = 3.6, 12.2 Hz), 2.67-2.76(2H, m), 3.05-3.16 (2H, m), 3.25 (2H, t, J = 4.2 Hz), 3.30-3.39 (3H, m),3.69 (4H, t, J = 5.2 Hz), 4.58 (1H, dd, J = 5.2, 12.2 Hz), 6.84 (1H, dd,J = 5.0, 6.7 Hz), 6.98 (1H, dt, J = 3.3, 7.9 Hz), 7.36-7.43 (2H, m),7.71 (1H, dd, J = 2.8, 11.3 Hz), 8.01 (1H, d, J = 5.0 Hz), 11.24 (1H,s). 15 (DMSO-d6): 0.90 (1H, d, J = 12.1 Hz), 1.04-1.15 (1H, m),1.59-1.69 (1H, m), 1.75 (1H, d, J = 12.1 Hz), 2.15 (3H, s), 2.36 (1H,dt, J = 2.6, 13.1 Hz), 2.58-2.75 (4H, m), 3.01-3.10 (1H, m), 3.25 (2H,t, J = 5.5 Hz), 3.30-3.35 (2H, m), 3.70 (4H, t, J = 4.9 Hz), 4.00 (1H,d, J = 12.5 Hz), 4.28 (1H, d, J = 12.5 Hz), 4.55 (1H, dd, J = 5.5, 13.1Hz), 6.40 (1H, d, J = 5.2 Hz), 6.55 (1H, s), 6.99 (1H, dt, J = 3.1, 7.8Hz), 7.38 (1H, dd, J = 5.2, 8.3 Hz), 7.72 (1H, dd, J = 3.1, 11.0 Hz),7.89 (1H, d, J = 5.7 Hz), 11.23 (1H, s). 16 (DMSO-d6): 0.90 (1H, d, J =11.5 Hz), 1.05-1.15 (1H, m), 1.60-1.70 (1H, m), 1.73-1.78 (1H, m), 2.09(3H, s), 2.224-2.36 (1H, m), 2.54-2.76 (4H, m), 2.96-3.11 (1H, m),3.21-3.27 (4H, m), 3.69 (4H, t, J = 4.5 Hz), 3.93 (1H, d, J = 12.7 Hz),4.20 (1H, d, J = 12.7 Hz), 4.50-4.59 (1H, m), 6.65 (1H, d, J = 8.7 Hz),6.98 (1H, dt, J = 3.0, 8.4 Hz), 7.28 (1H, dd, J = 2.2, 8.7 Hz), 7.37(1H, dd, J = 5.5, 8.4 Hz), 7.71 (1H, dd, J = 2.8, 10.7 Hz), 7.8 (1H, d,J = 2.1 Hz), 11.23 (1H, s) 17 (DMSO-d6) 1.01-1.05 (1H, m), 1.26-1.31(3H, m), 1.35-1.45 (1H, m), 1.90-1.98 (2H, m), 2.20 (3H, s), 2.25-2.30(1H, m), 2.43 (3H, s), 2.60-2.89 (6H, m), 3.14-3.23 (2H, m), 3.41-3.44(1H, m), 4.63-4.68 (1H, m), 6.89-6.92 (1H, m), 7.08 (1H, d, J = 7.5 Hz),7.28 (1H, d, J = 7.7 Hz), 7.48 (1H, dd, J = 1.0, 7.4 Hz), 8.01 (1H, s),8.07 (1H, dd, J = 1.6, 4.8 Hz), 11.83 (1H, s). 18 (DMSO-d6) 0.94-0.97(1H, m), 1.12-1.22 (1H, m), 1.30 (3H, t, J = 7.6 Hz), 1.66-1.77 (1H, m),1.80-1.84 (1H, m), 2.22 (3H, s), 2.36-2.41 (1H, m), 2.43 (3H, s),2.64-2.83 (6H, m), 3.10-3.19 (1H, m), 4.05 (1H, d, J = 13.2 Hz), 4.34(1H, d, J = 13.3 Hz), 4.60-4.64 (1H, m), 6.41 (1H, d, J = 5.0 Hz), 6.61(1H, s), 7.09 (1H, d, J = 7.5 Hz), 7.28 (1H, d, J = 7.9 Hz), 7.95 (1H,d, J = 5.0 Hz), 7.98 (1H, s), 11.84 (1H, s). 19 1.05-1.08 (1H, m), 1.29(3H, t, J = 7.7 Hz), 1.32-1.38 (1H, m), 1.75-1.78 (1H, m), 1.85-1.95(1H, m), 2.07 (3H, s), 2.27-2.31 (1H, m), 2.35 (3H, s), 2.56-2.86 (6H,m), 3.25-3.35 (1H, m), 3.84 (1H, d, J = 13.0 Hz), 4.15 (1H, d, J = 13.0Hz), 4.68 (1H, dd, J = 4.9, 13.3 Hz), 6.41 (1H, d, J = 8.6 Hz),6.93-6.96 (1H, m), 7.00-7.02 (1H, m), 7.16 (1H, dd, J = 2.3, 8.7 Hz),7.86 (1H, d, J = 2.2 Hz), 7.93 (1H, s), 9.15 (1H, br s). 20 0.93 (3H, t,J = 7.3 Hz), 1.05-1.08 (1H, m), 1.17-1.46 (3H, m), 1.68-1.79 (3H, m),1.84-1.94 (1H, m), 2.35 (3H, s), 2.36-2.40 (1H, m), 2.61-2.72 (4H, m),2.79-2.86 (1H, m), 3.26-3.35 (1H, m), 3.91 (1H, d, J = 13.2 Hz), 4.23(1H, d, J = 13.1 Hz), 4.65-4.69 (1H, m), 6.45-6.49 (2H, m), 6.93-7.03(2H, m), 7.31-7.35 (1H, m), 7.91 (1H, s) 8.02-8.04 (1H, m). 21 (DMSO-d6)0.97 (3H, t, J = 7.4 Hz), 1.03-1.04 (1H, m), 1.34-1.45 (1H, m),1.70-1.79 (2H, m), 1.89-1.98 (2H, m), 2.20 (3H, s), 2.25-2.30 (1H, m),2.43 (3H, s), 2.60-2.68 (4H, m), 2.77-2.86 (2H, m), 3.15-3.24 (2H, m),3.41-3.45 (1H, m), 4.60-4.68 (1H, m), 6.89-6.92 (1H, m), 7.06-7.13 (1H,m), 7.25-7.34 (1H, m), 7.48 (1H, d, J = 7.2 Hz), 8.01 (1H, d, J = 1.2Hz), 8.07 (1H, dd, J = 1.4, 4.7 Hz), 11.82 (1H, s). 22 0.77-0.83 (1H,m), 0.94 (3H, t, J = 7.3 Hz), 1.04-1.07 (1H, m), 1.26-1.37 (1H, m),1.68-1.77 (2H, m), 1.84-1.94 (1H, m), 2.13 (3H, s), 2.32-2.34 and2.38-2.39 (1H, m), 2.35 (3H, s), 2.60-2.71 (5H, m), 2.79-2.86 (1H, m),3.27-3.36 (1H, m), 3.90 (1H, d, J = 13.3 Hz), 4.21 (1H, d, J = 13.2 Hz),4.67-4.71 (1H, m), 6.30-6.32 (2H, m), 6.93-6.97 (1H, m), 7.00-7.02 (1H,m), 7.89-8.03 (2H, m). 23 0.92 (3H, t, J = 7.3 Hz), 1.04-1.07 (1H, m),1.17-1.46 (3H, m), 1.67-1.78 (3H, m), 1.84-1.94 (1H, m), 2.08 (3H, s),2.29-2.33 (1H, m), 2.35 (3H, s), 2.57-2.71 (4H, m), 2.78-2.86 (1H, m),3.25-3.34 (1H, m), 3.83 (1H, d, J = 13.0 Hz), 4.14 (1H, d, J = 13.1 Hz),4.67 (1H, dd, J = 5.0, 13.3 Hz), 6.43 (1H, d, J = 8.7 Hz), 6.93-7.03(2H, m), 7.16-7.19 (1H, m), 7.86 (1H, d, J = 2.2 Hz), 7.90 (1H, s). 24(DMSO-d6) 0.92-0.98 (5H, m), 1.13-1.23 (1H, m), 1.67-1.77 (1H, m),1.82-1.85 (1H, m), 1.96-2.03 (1H, m), 2.38-2.41 (1H, m), 2.43 (3H, s),2.66-2.69 (1H, m), 2.72-2.80 (3H, m), 3.07-3.16 (1H, m), 4.07 (1H, d, J= 13.4 Hz), 4.35 (1H, d, J = 13.3 Hz), 4.58-4.63 (1H, m), 6.60-6.63 (1H,m), 6.79 (1H, d, J = 8.7 Hz), 7.09 (1H, d, J = 7.6 Hz), 7.29 (1H, d, J =7.8 Hz), 7.49-7.53 (1H, m), 7.92 (1H, s), 8.09-8.11 (1H, m), 11.84 (1H,s). 25 (DMSO-d6) 0.90-1.00 (5H, m), 1.13-1.23 (1H, m), 1.67-1.84 (2H,m), 1.94-2.03 (1H, m), 2.16 (3H, s), 2.32-2.39 (1H, m), 2.43 (3H, s),2.61-2.68 (1H, m), 2.70-2.80 (3H, m), 3.07-3.16 (1H, m), 4.00 (1H, d, J= 13.2 Hz), 4.28 (1H, d, J = 13.2 Hz), 4.58-4.63 (1H, m), 6.72 (1H, d, J= 8.7 Hz), 7.09 (1H, d, J = 7.2 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.36 (1H,dd, J = 2.4, 8.7 Hz), 7.94 (2H, d, J = 2.4 Hz), 11.85 (1H, s). 26(DMSO-d6) 0.90-0.94 (4H, m), 1.07-1.17 (1H, m), 1.32-1.40 (2H, m),1.62-1.72 (3H, m), 1.77-1.79 (1H, m), 2.32-2.36 (1H, m), 2.38 (3H, s),2.60-2.77 (6H, m), 3.05-3.14 (1H, m), 4.00 (1H, d, J = 13.4 Hz), 4.29(1H, d, J = 13.4 Hz), 4.54-4.58 (1H, m), 6.54-6.57 (1H, m), 6.73 (1H, d,J = 8.8 Hz), 7.04 (1H, d, J = 7.4 Hz), 7.23 (1H, d, J = 7.8 Hz),7.43-7.48 (1H, m), 7.93 (1H, s), 8.03-8.05 (1H, m), 11.80 (1H, s). 27(DMSO-d6) 0.87 (1H, s), 0.92 (3H, t, J = 7.4 Hz), 1.07-1.17 (1H, m),1.30-1.39 (2H, m), 1.61-1.72 (3H, m), 1.75-1.77 (1H, m), 2.11 (3H, s),2.27-2.34 (1H, m), 2.38 (3H, s), 2.55-2.84 (6H, m), 3.05-3.14 (1H, m),3.93 (1H, d, J = 13.3 Hz), 4.21 (1H, d, J = 13.2 Hz), 4.53-4.58 (1H, m),6.63-6.71 (1H, m), 7.03 (1H, d, J = 7.5 Hz), 7.22 (1H, d, J = 7.7 Hz),7.30 (1H, dd, J = 2.3, 8.7 Hz), 7.88 (1H, d, J = 2.3 Hz), 7.94 (1H, s),11.78 (1H, s). 28 (DMSO-d6) 0.88 (1H, s), 0.91-0.93 (6H, m), 1.07-1.16(1H, m), 1.62-1.72 (1H, m), 1.76-1.79 (1H, m), 1.99-2.09 (1H, m),2.32-2.36 (1H, m), 2.38 (3H, s), 2.48 (2H, d, J = 7.2 Hz), 2.61-2.78(4H, m), 3.07-3.16 (1H, m), 3.99 (1H, d, J = 13.2 Hz), 4.28 (1H, d, J =13.3 Hz), 4.53-4.58 (1H, m), 6.54-6.57 (1H, m), 6.72 (1H, d, J = 8.6Hz), 7.04 (1H, d, J = 7.5 Hz), 7.23 (1H, d, J = 7.5 Hz), 7.43-7.48 (1H,m), 7.94 (1H, s), 8.03-8.05 (1H, m), 11.78 (1H, s). 29 (DMSO-d6) 0.92(1H, s), 0.96-0.98 (6H, m), 1.12-1.23 (1H, m), 1.67-1.82 (2H, m),2.04-2.13 (1H, m), 2.16 (3H, s), 2.28-2.39 (1H, m), 2.43 (3H, s), 2.54(2H, d, J = 7.3 Hz), 2.61-2.83 (4H, m), 3.12-3.21 (1H, m), 3.97 (1H, d,J = 13.3 Hz), 4.26 (1H, d, J = 13.2 Hz), 4.59-4.63 (1H, m), 6.71 (1H, d,J = 8.7 Hz), 7.09 (1H, d, J = 7.3 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.36(1H, dd, J = 2.3, 8.7 Hz), 7.93-7.99 (2H, m), 11.85 (1H, s). 301.10-1.13 (1H, m), 1.32-1.42 (1H, m), 1.69-1.77 (3H, m), 1.84-1.93 (1H,m), 2.07 (3H, s), 2.27 (3H, s), 2.33 (3H, s), 2.47 (4H, t, J = 4.9 Hz),2.54-2.67 (2H, m), 2.76-2.81 (1H, m), 3.17-3.26 (1H, m), 3.37 (4H, t, J= 4.7 Hz), 3.84 (1H, d, J = 11.8 Hz), 4.17 (1H, d, J = 11.4 Hz), 4.61(1H, d, J 8.4 Hz), 6.41 (1H, d, J = 8.6 Hz), 6.88-6.90 (1H, m),6.97-6.99 (1H, m), 7.16 (1H, dd, J = 2.2, 8.6 Hz), 7.86 (1H, d, J = 1.7Hz), 7.93 (1H, s), 8.91 (1H, s). 31 (DMSO-d6): d 0.93 (1H, d, J = 11.8Hz), 1.15-1.18 (1H, m), 1.61-1.71 (1H, m), 1.75 (1H, d, J = 10.5 Hz),2.31-2.33 (1H, m), 2.34 (3H, s), 2.58-2.75 (4H, m), 2.97-3.11 (1H, m),3.22-3.29 (4H, m), 3.69 (4H, t, J = 4.5 Hz), 4.01 (1H, d, J = 12.9 Hz),4.27 (1H, d, J = 12.9 Hz), 4.51-4.57 (1H, m), 6.53 (1H, dd, J = 5.2, 7.0Hz), 6.71 (1H, d, J = 8.6 Hz), 6.98 (1H, d, J = 7.7 Hz), 7.17 (1H, d, J= 7.7 Hz), 7.42-7.46 (1H, m), 7.86 (1H, s), 8.03 (1H, dd, J = 1.2, 4.9Hz), 11.10 (1H, s) 32 1.00-1.03 (1H, m), 1.07-1.12 (1H, m), 1.17-1.28(1H, m), 1.65-1.68 (1H, m), 1.75-1.82 (1H, m), 2.07 (3H, s), 2.25 (3H,s), 2.29-2.35 (1H, m), 2.49-2.72 (3H, m), 3.09-3.18 (1H, m), 3.27-3.29(4H, m), 3.54-3.68 (5H, m), 3.81 (1H, d, J = 13.1 Hz), 4.09 (1H H, d, J= 13.3 Hz), 4.52-4.56 (1H, m), 6.25 (1H, s), 6.26 (1H, s), 6.83-6.86(1H, m), 6.90-6.92 (1H, m), 7.66 (1H, s), 7.79 (1H, d, J = 5.6 Hz). 33(DMSO-d6): 0.94 (1H, d, J = 12.9 Hz), 1.08-1.18 (1H, m), 1.61-1.72 (1H,m), 1.77 (1H, d, J = 12.9 Hz), 2.32-2.37 (4H, m), 2.61-2.73 (4H, m),3.00-3.09 (2H, m), 3.29-3.36 (3H, m), 3.72 (4H, t, J = 5.1 Hz), 3.74(3H, s), 4.00 (1H, d, J = 13.1 Hz), 4.25 (1H, d, J = 13.1 Hz), 4.55 (1H,dd, J = 5.7, 12.0 Hz), 6.21-6.24 (2H, m), 7.06 (1H, d, J = 5.5 Hz), 7.26(1H, d, J = 6.6 Hz), 7.75 (1H, brs), 7.85 (1H, d, J = 6.6 Hz), 11.50(1H, brs). 34 (DMSO-d6): 0.93 (1H, d, J = 12.5 Hz), 1.11-1.23 (1H, m),1.63-1.77 (2H, m), 2.25 (1H, dt, J = 1.9, 11.9 Hz), 2.36 (3H, s), 2.55(1H, dt, J = 2.5, 12.5 Hz), 2.61-2.73 (3H, m), 3.00-3.09 (2H, m),3.24-3.46 (3H, m), 3.68 (3H, s), 3.69-3.73 (4H, m), 3.87 (1H, d, J =12.5 Hz), 4.11 (1H, d, J = 13.4 Hz), 4.54 (1H, dd, J = 5.0 Hz), 6.72(1H, d, J = 8.9 Hz), 7.00-7.05 (1H, m), 7.18 (1H, dd, J = 9.8 Hz),7.20-7.26 (1H, m), 7.72-7.77 (1H, m), 7.81 (1H, d, J = 3.1 Hz), 11.20(1H, brs). 35 (DMSO-d6) d 0.98 (1H, d, J = 11.3 Hz), 1.07-1.18 (1H, m),1.59-1.71 (1H, m), 1.81 (1H, d, J = 11.3 Hz), 2.35 (3H, s), 2.47-2.51(1H, m), 2.66-2.82 (4H, m), 2.92-3.05 (1H, m), 3.25-3.31 (4H, m), 3.70(4H, t, J = 4.9 Hz), 4.12 (1H, d, J = 13.1 Hz), 4.39 (1H, d, J = 13.1Hz), 4.52-4.56 (1H, m), 6.66 (1H, d, J = 9.2 Hz), 6.98 (1H, d, J = 7.6Hz), 7.18-7.20 (1H, m), 7.70 (1H, dd, J = 2.4, 9.2 Hz), 7.86 (1H, s),8.33 (1H, s), 11.10 (1H, s). 36 (DMSO-d6) 0.97-1.10 (2H, m), 1.59-1.69(1H, m), 1.80-1.83 (1H, m), 2.35 (3H, s), 2.66-2.84 (4H, m), 3.16 (2H,d, J = 5.4 Hz), 3.25-3.29 (4H, m), 3.69-3.71 (4H, m), 4.13 (1H, d, J =12.7 Hz), 4.41 (1H, d, J = 12.8 Hz), 4.53-4.56 (1H, m), 6.83 (1H, d, J =9.1 Hz), 6.98 (1H, d, J = 7.7 Hz), 7.19 (1H, d, J = 7.6 Hz), 7.76 (1H,dd, J = 2.3, 9.1 Hz), 7.86 (1H, s), 8.41 (1H, d, J = 2.1 Hz), 11.10 (1H,s). 37 (DMSO-d6): d 0.96 (1H, d, J = 12.1 Hz), 1.29-1.40 (1H, m),1.66-1.88 (6H, m), 2.13 (3H, s), 2.18-2.22 (1H, m), 2.36 (3H, s),2.47-2.53 (1H, m), 2.55-2.63 (1H, m), 2.70-2.81 (2H, m), 2.85-2.93 (1H,m), 3.11 (2H, d, J = 12.1 Hz), 3.34-3.45 (3H, m), 3.89-3.93 (2H, m),4.60 (1H, dd, J = 4.7, 13.1 Hz), 6.84 (1H, dd, J = 5.0, 7.0 Hz), 7.01(1H, dd, J = 1.8, 8.1 Hz), 7.20 (1H, d, J = 8.1 Hz), 7.41 (1H, d, J =7.0 Hz), 7.96 (1H, d, J = 1.3 Hz), 8.00 (1H, dd, J = 1.3, 5.0 Hz), 11.79(1H, s). 38 (DMSO-d6): d 0.89 (1H, d, J = 12.1 Hz), 1.07-1.17 (1H, m),1.59-1.87 (6H, m), 2.15 (3H, s), 2.29-2.37 (1H, m), 2.36 (3H, s), 2.61(1H, dt, J = 2.1, 12.5 Hz), 2.66-2.78 (3H, m), 2.86-2.94 (1H, m),3.03-3.12 (1H, m), 3.39-3.46 (2H, m), 3.89-3.94 (2H, m), 3.99 (1H, d, J= 13.1 Hz), 4.27 (1H, d, J = 13.1 Hz), 4.55 (1H, dd, J = 4.1, 13.1 Hz),6.39 (1H, d, J = 5.0 Hz), 6.54 (1H, s), 7.02 (1H, d, J = 7.7 Hz), 7.21(1H, d, J = 7.7 Hz), 7.88 (1H, d, J = 5.0 Hz), 7.95 (1H, s), 11.79 (1H,s). 39 (DMSO-d6): d 0.89 (1H, d, J = 12.1 Hz), 1.07-1.17 (1H, m),1.60-1.88 (6H, m), 2.09 (3H, s), 2.29 (1H, t, J = 12.5 Hz), 2.36 (3H,s), 2.58 (1H, t, J = 12.5 Hz), 2.64-2.79 (3H, m), 2.85-2.94 (1H, m),3.01-3.13 (1H, m), 3.42 (2H, t, J = 11.4 Hz), 3.90-3.94 (3H, m), 4.20(1H, d, J = 12.5 Hz), 4.56 (1H, d, J = 4.0, 13.2 Hz), 6.64 (1H, d, J =8.8 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.19 (1H, d, J = 7.9 Hz), 7.28 (1H,dd, J = 1.7, 8.8 Hz), 7.87 (1H, d, J = 1.7 Hz), 7.96 (1H, s), 11.78 (1H,s). 40 1.09 (1H, d, J = 12.6 Hz), 1.48-1.53 (1H, m), 1.78-2.08 (6H, m),2.24 (1H, t, J = 11.3 Hz), 2.35 (3H, s), 2.55-2.71 (3H, m), 2.84 (1H, t,J = 12.6 Hz), 3.01 (1H, t, J = 11.3 Hz), 3.30-3.40 (1H, m), 3.47-3.51(2H, m), 3.62 (1H, d, J = 12.7 Hz), 3.70 (3H, s), 3.86 (1H, d, J = 12.7Hz), 3.99-4.04 (2H, m), 4.70 (1H, dd, J = 5.2, 13.1 Hz), 6.69 (1H, dd, J= 4.7, 8.0 Hz), 6.89 (1H, d, J = 8.0 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.03(1H, d, J = 8.0 Hz), 7.71 (1H, dd, J = 1.5, 4.7 Hz), 8.01 (1H, s), 9.05(1H, s). 41 — 42 (DMSO-d6): d 0.89 (1H, d, J = 12.1 Hz), 1.10-1.22 (1H,m), 1.62-1.88 (6H, m), 2.25 (1H, dt, J = 2.3, 12.7 Hz), 2.35 (3H, s),2.54 (1H, dt, J = 2.3, 12.7 Hz), 2.61-2.79 (3H, m), 2.85-2.93 (1H, m),3.02-3.13 (1H, m), 3.42 (2H, tt, J = 2.1, 11.5 Hz), 3.68 (3H, s), 3.84(1H, d, J = 13.5 Hz), 3.90-3.93 (2H, m), 4.12 (1H, d, J = 13.5 Hz), 4.56(1H, dd, J = 4.7, 12.1 Hz), 6.71 (1H, d, J = 9.2 Hz), 7.01 (1H, dd, J =2.1, 7.9 Hz), 7.16-7.21 (2H, m), 7.80 (1H, d, J = 3.1 Hz), 7.95 (1H, d,J = 2.1 Hz), 11.80 (1H, s). 43 (DMSO-d6) 0.98-1.01 (1H, m), 1.15-1.24(1H, m), 1.67-1.82 (2H, m), 1.95-2.00 (4H, m), 2.05-2.09 (1H, m), 2.16(3H, s), 2.32-2.38 (1H, m), 2.42 (3H, s), 2.61-2.78 (4H, m), 3.07-3.14(2H, m), 3.59-3.63 (1H, m), 4.02 (1H, d, J = 13.1 Hz), 4.28 (1H, d, J =13.2 Hz), 4.57-4.61 (1H, m), 6.73 (1H, d, J = 8.6 Hz), 7.02 (1H, dd, J =1.4, 7.9 Hz), 7.24 (1H, d, J = 7.7 Hz), 7.36 (1H, dd, J = 2.3, 8.6 Hz),7.87-7.94 (2H, m), 10.83 (1H, s). 44 1.04-1.13 (1H, m), 1.23-1.46 (1H,m), 1.76-2.02 (2H, m), 2.37 (3H, s), 2.37-2.40 (1H, m), 2.60-2.77 (3H,m), 2.78-2.90 (1H, m), 3.19-3.39, (1H, m), 3.97 (1H, d, J = 13.3 Hz),4.27 (1H, d, J = 13.3 Hz), 4.69 (1H, dd, J = 4.7 Hz, 24.0 Hz), 6.44-6.57(2H, m), 7.02-7.18 (2H, m), 7.31-7.40 (1H, m), 8.07 (1H, m), 8.19 (1H,s), 10.40 (1H, br) 45 (MeOH, d3) d 1.03-1.08 (1H, m), 1.278-1.33 (1H,m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.37 (3H, s), 2.38-2.41 (1H, m),2.50-2.95 (4H, m), 3.29-3.31 (1H, m), 3.88 (1H, d, J = 13.4 Hz), 4.15(1H, d, J = 12.9 Hz), 4.65-4.69 (1H, m), 6.65 (1H, d, J = 8.7 Hz),7.28-7.36 (3H, m), 7.82 (1H, d, J 2.2 Hz), 8.00 (1H, brs). 46 1.10-1.14(1H, m), 1.34 (3H, t, J = 7.7 Hz), 1.36-1.39 (1H, m), 1.80-1.98 (2H, m),2.42 (1H, dt, J = 3.0, 12.9 Hz), 2.68-2.79 (6H, m), 3.28-3.34 (1H, m),3.99 (1H, d, J = 13.1 Hz), 4.29 (1H, d, J = 13.1 Hz), 4.70 (1H, dd, J =5.2, 13.1 Hz), 6.50-6.58 (2H, m), 7.09-7.18 (2H, m), 7.38 (1H, dt, J =2.0, 7.2 Hz), 8.17 (1H, d, J = 1.5 Hz), 8.21 (1H, s), 9.70 (1H, brs). 470.97 (3H, t, J = 7.4 Hz), 1.02-1.13 (1H, m), 1.33-1.44 (2H, m), 1.79(2H, q, J = 7.4 Hz), 1.82-1.93 (1H, m), 2.43 (1H, dt, J = 2.7, 12.6 Hz),2.68-2.74 (6H, m), 3.28-3.34 (1H, m), 3.97 (1H, d, J = 13.4 Hz), 4.29(1H, d, = 13.1 Hz), 4.74 (1H, dd, J = 5.0, 12.9 Hz), 6.52 (1H, t, J =2.9 Hz), 6.54 (1H, s), 7.13 (1H, s), 7.15 (1H, d, J = 2.2 Hz), 7.32 (1H,dt, J = 2.0, 7.2 Hz), 8.08 (1H, s), 8.20 (1H, brs), 9.40 (1H, brs). 480.97-0.99 (4H, m), 1.09-1.14 (1H, m), 1.34 (1H, dq, J = 4.0, 12.4 Hz),1.91-1.97 (3H, m), 2.40 (1H, dt, J = 2.7, 12.9 Hz), 2.62-2.69 (3H, m),2.82 (1H, dt, J = 3.5, 13.1 Hz), 3.20-3.30 (1H, m), 3.97 (1H, d, J =13.4 Hz), 4.29 (1H, d, J = 13.1 Hz), 4.69 (1H, dd, J = 4.7, 13.4 Hz),6.51-6.54 (2H, m), 7.12 (1H, s), 7.14 (1H, d, J = 2.2 Hz), 7.38 (1H, dt,J = 2.0, 6.9 Hz), 8.08 (1H, dd, J = 2.0, 5.4 Hz), 8.18 (1H, brs), 10.00(1H, brs). 49 1.11-1.53 (6H, m), 1.67-1.97 (5H, m), 2.07-2.10 (2H, m),2.43 (1H, dt, J = 2.7, 15.6 Hz), 2.68-2.95 (5H, m), 3.28-3.38 (1H, m),3.99 (1H, d, J = 13.4 Hz), 4.30 (1H, d, J = 12.6 Hz), 4.73 (1H, dd, J =5.2, 12.9 Hz), 6.50-6.64 (2H, m), 7.12 (1H, d, J = 8.4 Hz), 7.15 (1H,dd, J = 2.2, 8.4 Hz), 7.39 (1H, dt, J = 1.7, 8.9 Hz), 8.08 (1H, d, J =3.7 Hz), 8.28 (1H, d, J = 2.2 Hz), 9.17 (1H, brs). 50 1.16-1.26 (2H, m),1.35-1.97 (12H, m), 2.45 (1H, t, J = 11.6 Hz), 2.61-2.84 (1H, m),3.32-3.44 (4H, m), 4.00 (1H, d, J = 11.4 Hz), 4.34 (1H, m), 4.69 (1H,dd, J = 5.9, 13.1 Hz), 6.49-6.63 (3H, m), 7.05-7.13 (1H, m), 7.38 (1H,dt, J = 2.2, 8.9 Hz), 8.10 (1H, d, J = 3.3 Hz), 8.15-8.17 (1H, m). 511.16-1.24 (1H, m), 1.39-1.48 (1H, m), 1.72-2.01 (4H, m), 2.30-2.42 (6H,m), 2.48-2.87 (5H, m), 3.20-3.28 (1H, m), 3.42-3.51 (2H, m), 3.99 (1H,d, J = 12.1 Hz), 4.33 (1H, d, J = 12.1 Hz), 4.69-4.71 (1H, m), 6.50-6.67(3H, m), 7.09-7.14 (1H, m), 7.09-7.14 (1H, m), 7.30-7.44 (1H, m), 8.09(1H, d, J = 3.0 Hz), 8.18 (1H, s), 8.66 (1H, brs). 52 (DMSO-d6)0.96-0.99 (1H, m), 1.10-1.23 (1H, m), 1.67-1.77 (1H, m), 1.81 (1H, d, J= 11.7 Hz), 2.16 (3H, s), 2.29 (3H, s), 2.31-2.44 (1H, m), 2.52-2.57(4H, m), 2.65-2.81 (4H, m), 3.01-3.13 (2H, m), 3.35-3.43 (4H, m), 4.00(1H, d, J = 13.2 Hz), 4.27 (1H, d, J = 12.9 Hz), 4.61 (1H, dd, J = 4.3,12.6 Hz), 6.72 (1H, d, J = 8.6 Hz), 7.25 (1H, dd, J = 2.4, 8.3 Hz), 7.35(1H, dd, J = 2.0, 8.6 Hz), 7.43 (1H, d, J = 8.3 Hz), 7.94 (1H, s), 8.07(1H, d, J = 2.4 Hz), 11.25 (1H, s) 53 1.13-1.18 (1H, m), 1.31-1.41 (1H,m), 1.78-1.88 (2H, m), 1.96-2.00 (1H, m), 2.41 (1H, t, J = 11.9 Hz),2.65-2.76 (3H, m), 2.88-3.09 (1H, m), 3.37-3.46 (1H, m), 3.96 (1H, d, J= 12.6 Hz), 4.32 (1H, d, J = 12.6 Hz), 4.71 (1H, d, J = 8.7 Hz), 6.51(2H, d, J = 6.9 Hz), 7.14-7.17 (1H, m), 7.24 (1H, s), 7.34-7.42 (3H, m),7.97 (2H, d, J = 6.9 Hz), 8.07 (1H, s), 8.41 (1H, s), 10.84 (1H, s). 541.08-1.28 (1H, m), 1.29-1.51 (2H, m), 1.80-2.13 (2H, m), 2.40-2.50 (1H,m), 2.63-3.00 (3H, m), 3.35-3.54 (1H, m), 3.93-4.04 (1H, m), 4.25-4.38(1H, m), 4.68-4.84 (1H, m), 6.43-6.57 (2H, m), 7.01-7.11 (1H, m),7.13-7.32 (2H, m),7.33-7.49 (2H, m), 7.65-7.78 (2H, m), 8.08 (1H, d, J =1.9 Hz), 8.05 (1H, s), 10.40 (1H, s) 55 1.05-1.20 (1H, m), 1.30-1.48(1H, m), 1.50-1.72 (2H, m), 1.76-1.91 (1H, m), 1.92-2.09 (1H, m),2.31-2.55 (1H, m), 2.57-2.82 (2H, m), 2.83-3.03 (2H, m), 3.40-3.60 (1H,m), 3.87-4.03 (1H, m), 4.30-4.41 (1H, m), 4.75-4.93 (1H, m), 6.43-6.61(2H, m), 7.05-7.46 (4H, m), 8.10 (1H, s), 8.33-8.50 (2H, m), 9.67 (1H,s) 56 1.09-1.95 (4H, m), 2.43 (1H, t, J = 10.6 Hz), 2.62-2.94 (4H, m),3.20-3.31 (1H, m), 3.99 (1H, d, J = 12.9 Hz), 4.14 (1H, d, J = 5.0 Hz),4.33 (2H, t, J = 13.1 Hz), 4.67 (1H, dd, J = 5.9, 12.9 Hz), 6.50-6.70(3H, m), 7.13-7.41 (6H, m), 8.11 (2H, dd, J = 4.7, 16.6 Hz), 8.29 (1H,s), 8.97 (1H, s). 57 (CD3OD): 1.02-1.22 (1H, m), 1.22-1.43 (1H, m),1.72-1.98 (2H, m), 2.32-2.52 (1H, m), 2.58-2.95 (4H, m), 3.15-3.50 (5H,m), 3.68-3.90 (4H, m), 3.97 (1H, d, J = 12.9 Hz), 4.23 (1H, d, J = 12.9Hz), 4.65 (1H, dd, J = 5.7 Hz, 12.9 Hz), 6.57 (1H, t, J = 5.2 Hz), 6.71(1H, d, J = 5.2 Hz), 7.21 (1H, dd, J = 2.3 Hz, 8.4 Hz), 7.30 (1H, d, J =8.4 Hz), 7.40-7.60 (1H, m), 7.85-8.10 (2H, m). 58 (DMSO-d6): 0.90 (1H,d, J = 12.3 Hz), 1.05-1.17 (1H, m), 1.58-1.70 (1H, m), 1.75 (1H, d, J =12.3 Hz), 2.16 (3H, s), 2.37 (1H, t, J = 10.7 Hz), 2.61-2.74 (4H, m),2.96-3.08 (1H, m), 3.22-3.38 (3H, m), 3.70 (4H, t, J = 4.3 Hz),3.73-3.77 (1H, m), 4.00 (1H, d, J = 12.7 Hz), 4.28 (1H, d, J = 13.3 Hz),4.50-4.57 (1H, m), 6.40 (1H, d, J = 5.0 Hz), 6.56 (1H, s), 7.20 (1H, dd,J = 2.5, 8.4 Hz), 7.38 (1H, d, J = 8.4 Hz), 7.89 (1H, d, J = 5.0 Hz),8.01 (1H, s), 11.28 (1H, s). 59 (DMSO-d6): 0.85-1.0 (1H, m), 1.03-1.25(1H, m), 1.56-1.83 (2H, m), 2.10 (3H, s), 2.25-2.43 (1H, m), 2.55-2.58(3H, m), 2.92-3.13 (1H, m), 3.20-3.45 (5H, m), 3.63-3.70 (4H, m), 3.96(1H, d, J = 13.1 Hz), 4.23 (1H, d, J = 13.1 Hz), 4.57 (1H, dd, J = 5.0Hz, 13.1 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.20 (1H, dd, J = 2.7 Hz, 8.6Hz), 7.31 (1H, dd, J = 2.7 Hz, 8.6 Hz), 7.39 (1H, d, J = 8.6 Hz), 7.89(1H, d, J = 2.7 Hz), 8.03 (1H, d, J = 2.7 Hz), 11.29 (1H, brs). 601.01-1.30 (3H, m), 1.67-1.70 (1H, m), 1.76-1.84 (1H, m), 2.17 (3H, s),2.19-2.24 (1H, m), 2.44-2.58 (2H, m), 2.69-2.76 (1H, m), 3.13-3.22 (5H,m), 3.67-3.70 (4H, m), 3.86 (1H, d, J = 12.2 Hz), 4.17 (1H, d, J = 13.3Hz), 4.57-4.61 (1H, m), 6.17 (1H, d, J = 8.4 Hz), 6.24 (1H, d, J = 7.2Hz), 7.02 (2H, d, J = 4.0 Hz), 7.13-7.20 (2H, m), 8.05 (1H, d, J = 6.7Hz), 8.26 (1H, s). 61 1.05-1.08 (1H, m), 1.18 (1H, s), 1.30 (3H, t, J =7.6 Hz), 1.75-1.78 (1H, m), 1.85-1.92 (1H, m), 2.27 (3H, s), 2.30-2.34(1H, m), 2.36 (3H, s), 2.58-2.85 (6H, m), 3.28-3.37 (1H, m), 3.93 (1H,d, J = 13.2 Hz), 4.24 (1H, d, J = 13.0 Hz), 4.67-4.72 (1H, m), 6.28 (1H,d, J = 8.5 Hz), 6.34 (1H, d, J = 7.2 Hz), 6.96-7.04 (2H, m), 7.24 (1H,t, J = 7.8 Hz), 7.91 (1H, s). 62 0.94 (3H, t, J = 7.4 Hz), 1.04-1.07(1H, m), 1.26-1.36 (1H, m), 1.68-1.78 (3H, m), 1.84-1.94 (1H, m), 2.26(3H, s), 2.27-2.31 (1H, m), 2.35 (3H, s), 2.55-2.72 (5H, m), 2.79-2.89(1H, m), 3.27-3.36 (1H, m), 3.92 (1H, d, J = 13.1 Hz), 4.25 (1H, d, J =13.1 Hz), 4.66-4.70 (1H, m), 6.26 (1H, d, J = 8.5 Hz), 6.33 (1H, d, J =7.3 Hz), 6.94-6.97 (1H, m), 7.01-7.03 (1H, m), 7.19-7.23 (1H, m), 7.93(1H, s). 63 1.01-1.12 (2H, m), 1.25-1.37 (1H, m), 1.66-1.69 (1H, m),1.74-1.80 (1H, m), 2.17 (3H, s), 2.26 (3H, s), 2.45-2.58 (3H, m),2.68-2.75 (1H, m), 3.12-3.25 (5H, m), 3.55-3.70 (4H, m), 3.85 (1H, d, J= 12.0 Hz), 4.17 (1H, d, J = 12.5 Hz), 4.53-4.56 (1H, m), 6.17 (1H, d, J= 8.4 Hz), 6.24 (1H, d, J = 7.3 Hz), 6.81-6.84 (1H, m), 6.87-6.96 (1H,m), 7.11-7.15 (1H, m), 7.84 (1H, s), 8.58 (1H, s). 64 (DMSO-d6)0.93-0.96 (1H, m), 1.08-1.17 (1H, m), 1.63-1.72 (1H, m), 1.76-1.79 (1H,m), 2.34 (3H, s), 2.59-2.72 (4H, m), 2.98-3.11 (1H, m), 3.23-3.27 (4H,m), 3.29 (1H, s), 3.69-3.76 (7H, m), 3.98 (1H, d, J = 13.0 Hz), 4.24(1H, d, J = 13.2 Hz), 4.53-4.57 (1H, m), 5.93-5.96 (1H, m), 6.20-6.22(1H, m), 6.96-6.99 (1H, m), 7.17-7.24 (1H, m), 7.34-7.38 (1H, m), 7.86(1H, d, J = 1.4 Hz), 11.10 (1H, s). 65 (DMSO-d6): 0.91 (1H, d, J = 12.1Hz), 1.07-1.17 (1H, m), 1.59-1.88 (6H, m), 2.23 (3H, s), 2.27-2.38 (1H,m), 2.36 (3H, s), 2.58 (1H, t, J = 12.9 Hz), 2.65-2.79 (3H, m),2.86-2.93 (1H, m), 3.04-3.13 (1H, m), 3.42 (2H, t, J = 11.2 Hz),3.90-3.93 (2H, m), 3.99 (1H, d, J = 13.1 Hz), 4.27 (1H, d, J = 13.1 Hz),4.56 (1H, dd, J = 4.7, 13.1 Hz), 6.41 (1H, d, J = 7.3 Hz), 6.48 (1H, d,J = 7.3 Hz), 7.01 (1H, d, J = 7.6 Hz), 7.20 (1H, d, J = 7.6 Hz), 7.32(1H, t, J = 7.6 Hz), 7.96 (1H, s), 11.78 (1H, s). 66 1.06 (1H, d, J =12.4 Hz), 1.25-1.35 (1H, m), 1.77-1.96 (6H, m), 2.30 (1H, t, J = 12.4Hz), 2.37 (3H, s), 2.55-2.68 (3H, m), 2.84 (1H, dt, J = 3.3, 13.3 Hz),3.07 (1H, brs), 3.26-3.35 (1H, m), 3.47 (2H, t, J = 11.3 Hz), 3.72 (3H,s), 3.94 (1H, d, J = 13.0 Hz), 4.01 (2H, d, J = 11.0 Hz), 4.23 (1H, d, J= 13.0 Hz), 4.64 (1H, dd, J = 5.7, 13.0 Hz), 5.91 (1H, d, J = 7.8 Hz),5.99 (1H, d, J = 7.8 Hz), 6.98 (1H, d, J = 7.7 Hz), 7.04 (1H, d, J = 7.7Hz), 7.24 (1H, t, J = 7.7 Hz), 7.94 (1H, brs), 9.83 (1H, brs). 67(DMSO-d6) d 0.91 (1H, d, J = 12.3 Hz), 1.04-1.15 (1H, m), 1.59-1.70 (1H,m), 1.77 (1H, d, J = 12.3 Hz), 2.23 (3H, s), 2.31-2.38 (1H, m),2.58-2.74 (4H, m), 2.98-3.08 (1H, m), 3.25 (2H, t, J = 4.5 Hz),3.28-3.38 (1H, m), 3.69 (4H, t, J = 4.5 Hz), 3.68-3.76 (1H, m), 4.01(1H, d, J = 13.3 Hz), 4.28 (1H, d, J = 13.3 Hz), 4.52-4.58 (1H, m), 6.41(1H, d, J = 7.2 Hz), 6.50 (1H, d, J = 8.5 Hz), 7.20 (1H, dd, J = 2.6,8.5 Hz), 7.30-7.39 (2H, m), 8.01 (1H, d, J = 2.6 Hz), 11.28 (1H, s). 680.99-1.12 (1H, m), 1.20-1.30 (1H, m), 1.64-1.67 (1H, m), 1.74-1.85 (1H,m), 2.20-2.27 (1H, m), 2.48-2.54 (3H, m), 2.64-2.71 (1H, m), 3.10-3.19(1H, m), 3.23-3.25 (4H, m), 3.64 (3H, s), 3.67-3.69 (4H, m), 3.87 (1H,d, J = 13.2 Hz), 4.15 (1H, d, J = 13.2 Hz), 4.53-4.57 (1H, m), 5.84 (1H,d, J = 7.9 Hz), 5.91 (1H, d, J = 8.1 Hz), 6.95-7.01 (2H, m), 7.17 (1H,t, J = 8.0 Hz), 8.01 (1H, s), 8.63 (1H, s). 69 (DMSO-d6) 1.07-1.10 (1H,m), 1.38-1.46 (1H, m), 1.92-2.02 (2H, m), 2.24 (3H, s), 2.28-2.31 (1H,m), 2.42 (3H, s), 2.58-2.80 (4H, m), 2.93 (1H, d, J = 11.6 Hz),3.14-3.17 (2H, m), 3.32 (4H, s), 3.75-3.77 (4H, m), 4.65 (1H, d, J = 9.7Hz), 7.06 (1H, d, J = 6.9 Hz), 7.17 (1H, d, J = 4.8 Hz), 7.26 (1H, d, J= 6.8 Hz), 7.93 (1H, s), 8.13 (1H, d, J = 4.7 Hz), 8.15 (1H, s), 11.21(1H, s). 70 (DMSO-d6): 0.97 (1H, d, J = 12.2 Hz), 1.18-1.29 (1H, m),1.75-1.81 (2H, m), 2.17 (3H, s), 2.19-2.27 (1H, m), 2.34 (3H, s),2.51-2.73 (4H, m), 2.97-3.12 (2H, m), 3.25 (2H, t, J = 4.6 Hz),3.28-3.35 (2H, m), 3.46-3.50 (1H, m), 3.70 (4H, t, J = 4.6 Hz), 4.56(1H, dd, J = 4.6, 12.5 Hz), 6.97 (1H, dd, J = 2.1, 8.9 Hz), 7.03 (1H,s), 7.18 (1H, d, J = 7.3 Hz), 7.75 (1H, s), 7.86 (1H, d, J = 1.7 Hz),7.98 (1H, d, J = 2.5 Hz), 11.11 (1H, brs) 71 1.14-1.26 (2H, m),1.49-1.57 (3H, m), 1.81 (1H, d, J = 12.8 Hz), 2.01-2.15 (2H, m), 2.35(3H, s), 2.38 (3H, s), 2.52-2.63 (1H, m), 2.74-2.86 (1H, m), 3.06 (1H,d, J = 11.7 Hz), 3.26-3.34 (5H, m), 3.78 (4H, t, J = 4.7 Hz), 4.66-4.71(1H, m), 6.92-7.06 (4H, m), 7.93 (1H, s), 8.07 (1H, dd, J = 1.3, 4.6Hz), 8.58 (1H, s). 72 1.08-1.20 (1H, m), 1.80-1.90 (1H, m), 2.01-2.16(1H, m), 2.20-2.33 (1H, m), 2.45 (3H, s), 2.48-2.63 (2H, m), 2.67-2.93(2H, m), 3.29-3.41 (2H, m), 3.60-3.74 (2H, m), 4.77, (1H, dd, J = 4.7,13.1 Hz), 6.70-6.85 (3H, m), 7.08-7.20 (4H, m), 8.25 (1H, s), 8.99 (1H,s) 73 (DMSO-d6) 0.80-1.02 (1H, m), 1.10-1.35 (3H, m), 1.24 (3H, t, J =7.7 Hz), 1.67-1.92 (2H, m), 2.23 (1H, t, J = 12.1 Hz), 2.40-2.90 (2H,m), 2.65 (2H, q, J = 7.7 Hz), 2.95-3.20 (1H, m), 3.20-3.54 (1H, m), 3.68(1H, d, J = 12.1 Hz), 4.57 (1H, dd, J = 4.7 Hz, 12.9 Hz), 6.70 (1H, t, J= 7.2 Hz), 6.82 (2H, d, J = 7.2 Hz), 7.13 (2H, t, J = 7.2 Hz), 7.25 (1H,dd, J = 1.7 Hz, 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 8.08 (1H, dd, J = 1.7Hz), 12.10 (1H, brs) 74 (DMSO-d6) 0.80-1.00 (1H, m), 0.92 (3H, t, J =7.4 Hz), 1.10-1.35 (1H, m), 1.60-1.90 (2H, m), 1.69 (2H, s, J = 7.4 Hz),2.23 (1H, t, J = 12.1 Hz), 2.40-2.65 (2H, m), 2.59 (2H, t, J = 7.4 Hz),2.65-2.90 (2H, m), 2.87-3.18 (1H, m), 3.24-3.50 (1H, m), 3.69 (1H, d, J= 12.1 Hz), 4.58 (1H, dd, J = 4.0 Hz, 15.1 Hz), 6.70 (1H, t, J = 7.2Hz), 6.82 (2H, d, J = 8.2 Hz), 7.13 (2H, t, J = 7.2 Hz), 7.24 (1H, dd, J= 2.5 Hz, 8.4 Hz), 7.41 (1H, d, J = 8.4 Hz), 8.09 (1H, d, J = 2.5 Hz),11.94 (1H, s). 75 (DMSO-d6) 0.74-1.03 (5H, m), 1.10-1.32 (1H, m),1.675-1.87 (2H, m), 1.87-2.00 (1H, m), 2.12-2.32 (1H, m), 2.40-2.65 (2H,m), 2.65-2.88 (2H, m), 2.88-3.20 (1H, m), 3.43 (1H, d, J = 12.4 Hz),3.68 (1H, d, J = 12.4 Hz), 4.57 (1H, d, J = 9.7 Hz), 6.69 (1H, t, J =7.4 Hz), 6.82 (2H, d, J = 7.4 Hz), 7.04-7.20 (2H, m), 7.23 (1H, dd, J =2.2 Hz, 8.2 Hz), 7.41 (1H, d, J = 8.4 Hz), 8.05 (1H, brs), 11.92 (1H,brs). 76 (DMSO-d6) 0.84-1.05 (1H, m), 1.10-1.62 (6H, m), 1.62-2.10 (8H,m), 2.23 (1H, t, J = 11.9 Hz), 2.40-2.90 (4H, m), 2.95-3.20 (1H, m),3.24-3.55 (1H, m), 3.68 (1H, d, J = 11.9 Hz), 4.44-4.70 (1H, m), 6.70(1H, t, J = 6.9 Hz), 6.82 (2H, d, J = 7.7 Hz), 7.05-7.33 (1H, m), 7.12(2H, t, J = 6.9 Hz), 7.34-7.50 (1H, m), 8.06-8.20 (1H, m), 11.87 (1H,s). 77 (DMSO-d6) 0.90-1.05 (1H, m), 1.10-1.36 (2H, m), 1.40-1.70 (6H,m), 1.70-1.90 (2H, m), 2.23 (1H, t, J = 12.4 Hz), 2.40-2.80 (4H, m),2.90-3.27 (1H, m), 3.20-3.55 (4H, m), 3.69 (1H, d, J = 12.4 Hz), 4.55(1H, dd, J = 5.0 Hz, 12.1 Hz), 6.69 (1H, t, J = 7.2 Hz), 6.83 (2H, d, J= 7.2 Hz), 7.14 (2H, t, J = 7.2 Hz), 7.20 (1H, dd, J = 2.5 Hz, 8.4 Hz),7.39 (1H, d, J = 8.4 Hz), 7.90-8.05 (1H, m), 11.20 (1H, brs). 78(DMSO-d6) 0.90-1/05 (1H, m), 1.13-1.35 (1H, m), 1.70-1.88 (2H, m), 2.23(3H, s), 2.33-2.80 (8H, m), 2.90-3.15 (1H, m), 3.15-3.55 (6H, m), 3.69(1H, d, J = 12.4 Hz), 4.44-4.65 (1H, m), 6.70 (1H, t, J = 7.2 Hz), 6.82(2H, d, J = 7.2 Hz), 7.13 (2H, t, J = 7.2 Hz), 7.19 (1H, dd, J = 2.5 Hz,8.4 Hz), 7.38 (1H, d, J = 8.4 Hz), 7.97-8.07 (1H, m), 11.23 (1H, s) 79(DMSO-d6) 0.85-1.05 (1H, m), 1.10-1.38 (1H, m), 1.50-1.95 (3H, m), 2.22(1H, t, J = 12.6 Hz), 2.40-3.10 (4H, m), 3.20-3.50 (1H, m), 3.55-3.85(1H, m), 4.50-4.75 (1H, m), 6.62-6.87 (1H, m), 6.80 (2H, d, J = 8.2 Hz),6.87-7.02 (1H, m), 7.04-7.26 (1H, m), 7.11 (2H, t, J = 8.2 Hz),7.27-7.60 (2H, m), 7.49 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 8.2 Hz),8.26 (1H, s). 80 1.10-1.20 (1H, m), 1.30-1.48 (1H, m), 1.80-1.91 (1H,m), 2.00-2.19 (1H, m), 2.20-2.32 (1H, m), 2.50-2.64 (2H, m), 2.87 (1H,s), 2.90-2.96 (2H, m), 3.28-3.40 (1H, m), 3.41-3.60 (1H, m), 3.61-3.70(1H, m), 4.80-4.92 (1H, m), 6.72-6.88 (3H, m), 7.08-7.38 (6H, m),8.35-8.44 (2H, m), 9.87 (1H, d, J = 6.9 Hz) 81 1.09-1.28 (1H, m),1.39-1.60 (2H, m), 1.77-1.93 (1H, m), 1.95-2.17 (1H, m), 2.18-2.36 (1H,m), 2.49-2.69 (2H, m), 2.80-3.04 (2H, m), 3.30-3.54 (2H, m), 3.59-3.74(1H, m), 4.70-4.84 (1H, m), 6.70-6.90 (3H, m), 7.00-7.10 (1H, m),7.11-7.21 (4H, m), 7.33-7.48 (1H, m), 7.60-7.78 (2H, m), 8.36 (1H, s) 82(CD3OD) 1.00-1.20 (1H, m), 1.20-1.54 (1H, m), 1.72-2.10 (3H, m),2.12-2.32 (1H, m), 2.42-3.08 (3H, m), 3.22-3.50 (1H, m), 3.55-3.85 (2H,m), 4.06 (2H, s), 4.67 (1H, dd, J = 5.7 Hz, 12.4 Hz), 6.71-6.92 (3H, m),6.92-7.06 (1H, m), 7.09-7.50 (9H, m), 8.09 (1H, brs). 83 (DMSO-d6)0.90-1.05 (1H, m), 1.18-1.42 (1H, m), 1.60-1.95 (2H, m), 2.14-2.35 (2H,m), 2.29 (3H, s), 2.40-2.85 (4H, m), 2.90-3.20 (2H, m), 4.60 (1H, dd, J= 4.0 Hz, 13.4 Hz), 6.75-7.17 (5H, m), 7.25 (1H, dd, J = 2.5 Hz, 8.4Hz), 7.42 (1H, d, J = 8.4 Hz), 8.04 (1H, d, J = 2.5 Hz). 84 (DMSO-d6)0.84-0.95 (1H, m), 1.08-1.30 (2H, m), 1.64-1.85 (2H, m), 2.18-2.36 (1H,m), 2.29 (3H, s), 2.45-2.85 (3H, m), 2.95-3.18 (1H, m), 3.48 (1H, d, J =12.6 Hz), 3.74 (1H, d, J = 12.6 Hz), 4.58 (1H, dd, J = 4.2 Hz, 12.6 Hz),6.38-6.52 (1H, m), 6.54-6.68 (2H, m), 7.05-7.20 (1H, m), 7.25 (1H, dd, J= 2.5 Hz, 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 8.05 (1H, m). 85 (DMSO-d6)1.30-1.54 (1H, m), 1.63-1.88 (2H, m), 2.05-2.48 (2H, m), 2.60-2.90 (1H,m), 2.82 (3H, s), 2.90-3.17 (2H, m), 3.17-3.40 (2H, m), 3.50-3.72 (1H,m), 3.95-4.25 (1H, m), 5.00-5.20 (1H, m), 7.20-7.42 (2H, m), 7.42-7.60(2H, m), 7.62-7.88 (1H, m), 7.88-8.05 (1H, m), 8.56 (1H, m). 86(DMSO-d6) 0.90-1.05 (1H, m), 1.20-1.45 (1H, m), 1.80-2.00 (2H, m),2.14-2.35 (1H, m), 2.28 (3H, s), 2.40-2.62 (2H, m), 2.65-2.90 (2H, m),2.90-3.40 (3H, m), 4.52-4.70 (1H, m), 6.90-7.09 (2H, m), 7.12-7.30 (2H,m), 7.30-7.38 (1H, m), 7.43 (1H, d, J = 8.4 Hz), 8.05 (1H, s), 12.0 (1H,brs). 87 1.10-1.54 (1H, m), 1.42-4.17 (1H, m), 1.81-1.86 (1H, m),2.00-2.06 (1H, m), 2.31-2.38 (1H, m), 2.42 (3H, m), 2.45-2.62 (2H, m),2.71-2.86 (2H, m), 3.33-3.42 (2H, m), 3.67 (1H, d, J = 13.1 Hz), 4.77(1H, dd, J = 4.9, 13.7 Hz), 6.73-6.74 (3H, m), 7.13-7.25 (3H, m), 8.21(1H, s), 9.00 (1H, brs). 88 (DMSO-d6) 0.80-0.98 (1H, m), 1.08-1.30 (1H,m), 1.65-1.90 (2H, m), 2.15-2.36 (1H, m), 2.28 (3H, s), 2./42-2.67 (2H,m), 2.67-2.90 (2H, m), 2.95-3.18 (1H, m), 3.22-3.50 (1H, m), 3.68 (1H,d, J = 12.6 Hz), 4.50-4.65 (1H, m), 6.83 (2H, d, J = 8.7 Hz), 7.14 (2H,d, J = 8.7 Hz), 7.19-7.30 (1H, m), 7.42 (1H, d, J = 8.2 Hz), 8.07 (1H,s), 11.96 (1H, brs). 89 (DMSO-d6) 1.02-1.15 (1H, m), 1.40-1.60 (1H, m),1.80-1.95 (1H, m), 1.95-2.30 (2H, m), 2.20 (3H, s), 2.38 (3H, s),2.30-2.53 (1H, m), 2.53-2.67 (1H, m), 2.72-3.00 (3H, m), 3.00-3.13 (1H,m), 3.25-3.42 (1H, m), 4.65-4.77 (1H, m), 6.80-6.93 (2H, m), 6.97-7.11(2H, m), 7.17-7.41 (2H, m), 8.01 (1H, s). 90 (DMSO-d6) d 0.89-0.93 (1H,m), 1.19-2.23 (1H, m), 1.75-1.80 (2H, m), 2.19 (3H, s), 2.28 (3H, s),2.44-2.59 (2H, m), 2.74-2.80 (1H, m), 2.93 (1H, m), 3.03-3.08 (1H, m),3.35-3.43 (1H, m), 3.67 (2H, d, J = 12.4 Hz), 4.56 (1H, dd, J = 4.5,12.6 Hz), 6.52 (1H, d, J = 7.2 Hz), 6.59-6.64 (1H, m), 7.01 (1H, t, J =7.9 Hz), 7.22-7.27 (2H, m), 7.43 (1H, d, J = 8.4 Hz), 8.06 (1H, s),11.98 (1H, s). 91 (DMSO-d6) 0.85-0.98 (1H, m), 1.13-1.33 (1H, m),1.68-1.88 (2H, m), 2.05-2.23 (1H, m), 2.15 (3H, s), 2.28 (3H, s),2.36-2.64 (2H, m), 2.65-2.85 (1H, m), 2.98-3.18 (1H, m), 3.22-3.42 (1H,m), 3.59 (1H, d, J = 12.4 Hz), 4.58 (1H, dd, J = 4.2, 13.1 Hz), 6.71(2H, d, J = 8.4 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 2.7 Hz,8.4 Hz), 7.40 (1H, d, J = 8.4 Hz), 8.08 (1H, d, J = 2.7 Hz), 11.96 (1H,s). 92 (DMSO-d6) 0.87-1.00 (1H, m), 1.22-1.42 (1H, m), 1.74-1.96 (2H,m), 1.98-2.15 (1H, m), 2.22-2.40 (1H, m), 2.29 (3H, m), 2.65-2.87 (2H,m), 2.88-2.98 (1H, m), 2.98-3.20 (2H, m), 3.60-3.84 (1H, m), 3.72 (3H,s), 4.54-4.68 (1H, m), 6.70-7.00 (4H, m), 7.12-7.34 (2H, m), 7.41 (1H,d, J = 8.4 Hz), 7.92-8.20 (1H, m), 11.97 (1H, brs). 93 (DMSO-d6)0.98-1.15 (1H, m), 1.22-1.52 (2H, m), 1.73-2.06 (2H, m), 2.10-2.30 (1H,m), 2.30-2.70 (2H, m), 2.40 (3H, s), 2.75-3.00 (2H, m), 3.12-3.45 (2H,m), 3.55-3.80 (1H, m), 3.69 (3H, s), 4.60-4.78 (1H, m), 6.25-6.52 (2H,m), 6/43 (1H, d, J = 8.9 Hz), 7.04 (1H, t, J = 8.9 Hz), 7.20-7.40 (1H,m), 7.27 (1H, dd, J = 2.2, 8.4 Hz), 7.99 (1H, d, J = 2.2 Hz). 94 (CD3OD)1.04-1.15 (1H, m), 1.35-1.55 (1H, m), 1.82-2.06 (2H, m), 2.06-2.22 (1H,m), 2.30-2.50 (1H, m), 2.38 (3H, s), 2.50-2.65 (1H, m), 2.75-3.00 (2H,m), 3.17 (1H, d, J = 12.1 Hz), 3.24-3.40 (1H, m), 3.45 (1H, d, J = 12.1Hz), 3.58 (3H, s), 4.64-4.76 (1H, m), 6.74 (2H, d, J = 9.2 Hz), 6.83(2H, d, J = 9.2 Hz), 7.25 (1H, dd, J = 2.5 Hz, 8.4 Hz), 7.33 (1H, d, J =8.4 Hz), 8.01 (1H, brs). 95 1.15 (3H, t, J = 7.4 Hz), 1.16-1.18 (1H, m),1.40-1.58 (1H, m), 1.80-1.91 (1H, m), 2.05-2.31 (2H, m), 2.46 (3H, s),2.47-2.49 (1H, m), 2.52 (2H, q, J = 7.4 Hz), 2.70-2.94 (2H, m),3.26-3.46 (2H, m), 3.56-3.68 (1H, m), 4.73-4.82 (1H, m), 6.75 (2H, d, J= 8.4 Hz), 7.02 (2H, d, J = 8.7 Hz), 7.10-7.23 (3H, m), 8.21 (1H, s),9.00 (1H, brs) 96 0.88 (3H, t, J = 7.4 Hz), 0.98-1.21 (2H, m), 1.41-1.63(3H, m), 1.78-2.32 (4H, m), 2.44 (3H, s), 2.47-2.60 (1H, m), 2.61-2.92(2H, m), 3.23-3.42 (2H, m), 3.56-3.70 (1H, m), 4.70-4.80 (1H, m),5.30-5.58 (1H, m), 6.73 (1H, d, J = 8.6 Hz), 6.80-6.89 (1H, m),6.92-7.00 (1H, m), 7.03-7.20 (3H, m), 8.24 (1H, s), 9.57 (1H, s) 971.15-1.22 (6H, m), 1.76-2.10 (3H, m), 2.18-2.34 (1H, m), 2.44 (3H, s),2.45-2.60 (1H, m), 2.61-2.91 (3H, m), 3.25-3.40 (1H, m), 3.53-3.71 (2H,m), 4.69-5.80 (1H, m), 5.50-5.73 (1H, m), 6.75 (2H, d, J = 8.7 Hz), 6.86(2H, d, J = 8.7 Hz), 6.94-7.18 (4H, m), 8.19 (1H, s) 98 1.37-1.59 (2H,m), 1.72-1.88, (2H, m), 2.40-2.57 (2H, m), 2.63-2.73 (1H, m), 3.72 (3H,s), 3.81 (1H, d, J = 14.6 Hz), 4.53-4.73 (2H, m), 5.62 (1H, d, J = 14.6Hz), 5.98 (1H, s), 6.39 (1H, dd, J = 4.6, 4.6 Hz), 7.00-7.11 (2H, m),7.16-7.21 (2H, m), 7.26-7.32 (1H, m), 8.22 (2H, d, J = 4.6 Hz) 991.24-1.59 (4H, m), 1.71-2.10 (10H, m), 2.43-2.62 (2H, m), 2.69-2.80 (1H,m), 3.72-3.78 (1H, m), 3.82 (1H, d, J = 14.6 Hz), 4.54-4.76 (2H, m),5.64 (1H, d, J = 14.6 Hz), 5.84 (1H, s), 6.66 (1H, d, J = 4.9 Hz),7.00-7.09 (2H, m), 7.18-7.22 (2H, m), 7.27-7.33 (1H, m), 8.40 (1H, d, J= 4.9 Hz) 100 1.41-1.61 (1H, m), 1.68-1.93 (3H, m), 2.39-2.49 (1H, m),2.50-2.60 (1H, m), 2.64-2.74 (1H, m), 3.70 (3H, s), 3.79 (1H, d, J =14.6 Hz), 4.55-4.74 (2H, m), 5.58 (1H, d, J = 14.6 Hz), 6.12 (1H, s),6.41 (1H, dd, J = 4.7, 4.7 Hz), 6.71-6.81 (2H, m), 7.13-7.18 (2H, m),8.23 (2H, d, J = 4.7 Hz) 101 1.41 (3H, t, J = 7.3 Hz), 1.42-1.58 (2H,m), 2.41-2.52 (1H, m), 2.56-2.66 (1H, m), 2.71-2.81 (1H, m), 3.80 (1H,d, J = 14.3 Hz), 4.02 (2H, q, J = 7.3 Hz), 4.57-4.77 (2H, m), 5.60 (1H,d, J = 14.3 Hz), 5.94 (1H, s), 6.67 (1H, d, J = 4.7 Hz), 6.70-6.75 (1H,m), 6.77-6.81 (1H, m), 7.14-7.19 (1H, m), 7.20 (1H, s), 8.41 (1H, d, J =4.7 Hz) 102 1.38-1.56 (2H, m), 1.71-1.88 (2H, m), 2.35 (3H, s),2.44-2.76 (3H, m), 3.70 (3H, s), 3.78 (1H, d, J = 14.6 Hz), 4.53-4.73(2H, m), 5.60 (1H, d, J = 14.6 Hz), 5.84 (1H, s), 6.39 (1H, dd, J = 4.9,4.9 Hz), 6.82 (1H, d, J = 1.3 Hz), 6.86 (1H, dd, J = 1.3, 7.9 Hz), 7.06(1H, d, J = 7.9 Hz), 7.16 (1H, s), 8.22 (2H, d, J = 4.9 Hz) 1031.42-1.92 (4H, m), 2.41-2.77 (3H, m), 3.70 (3H, s), 3.78 (1H, d, J =14.6 Hz), 4.56-4.74 (2H, m), 5.58 (1H, d, J = 14.6 Hz), 6.09 (1H, s),6.40 (1H, dd, J = 4.9, 4.9 Hz), 7.01-7.05 (1H, m), 7.10-7.18 (2H, m),7.25-7.26 (1H, m), 8.24 (2H, d, J = 4.9 Hz) 104 1.30-2.10 (4H, m),2.35-3.10 (3H, m), 3.83 (1H, d, J = 14.8 Hz), 4.58 (1H, d, J = 13.6 Hz),4.71 (1H, d, J = 13.6 Hz), 5.64 (1H, d, J = 14.8 Hz), 6.32 (1H, s), 6.38(1H, t, J = 9.4 Hz), 6.87 (1H, s), 6.99 (1H, d, J-8.4 Hz), 7.10 (1H, d,J = 8.4 Hz), 7.25-7.60 (6H, m), 8.21 (2H, d, J = 4.7 Hz) 105 1.15 (3H,t, J = 7.7 Hz), 1.40-1.91 (4H, m), 2.42 (2H, q, J = 7.7 Hz), 2.40-2.49(1H, m), 2.52-2.62 (1H, m), 2.65-2.76 (1H, m), 3.86 (1H, d, J = 14.6Hz), 4.53-4.71 (2H, m), 5.70 (1H, d, J = 14.6 Hz), 6.14 (1H, s), 6.88(1H, d,, J = 2.2 Hz), 7.03 (1H, dd, J = 2.2, 8.4 Hz), 7.15 (1H, d, J =8.4 Hz), 7.39 (1H, s), 7.43-7.47 (3H, m), 7.53-7.61 (2H, m), 8.08-8.15(2H, m) 106 1.24-2.03 (4H, m), 2.42-2.53 (2H, m), 2.62-2.71 (1H, m),3.72 (3H, s), 3.82 (1H, d, J = 14.3 Hz), 4.09-4.23 (2H, m), 5.62 (1H, d,J = 14.3 Hz), 6.04 (1H, s), 6.50-6.58 (2H, m), 7.00-7.08 (2H, m),7.18-7.31 (3H, m), 7.36-7.42 (1H, m), 8.10 (1H, d, J = 4.2 Hz) 107(DMSO-d6) 1.23 (3H, t, J = 7.1 Hz), 1.20-1.27 (2H, m), 1.53-1.69 (2H,m), 2.09 (3H, s), 2.3-2.41 (2H, m), 2.54 (1H, dt, J = 2.1, 12.5 Hz),3.73 (1H, d, J = 14.3 Hz), 4.01-4.13 (3H, m), 4.16 (1H, d, J = 13.4 Hz),5.34 (1H, d, J = 14.3 Hz), 6.66 (1H, d, J = 8.8 Hz), 6.81-6.87 (1H, m),7.10 (1H, s), 7.15 (1H, dd, J = 3.3, 10.6 Hz), 7.28-7.33 (2H, m), 7.87(1H, d, J = 2.3 Hz), 8.53 (1H, s). 108 (DMSO-d6) 1.21-1.28 (2H, m), 1.59(9H, s), 1.60-1.71 (2H, m), 2.09 (3H, s), 2.34-2.42 (2H, m), 2.50-2.58(1H, m), 3.74 (1H, d, J = 14.6 Hz), 4.03 (1H, d, J = 13.1 Hz), 4.15 (1H,d, J = 13.1 Hz), 5.34 (1H, d, J = 14.6 Hz), 6.66 (1H, d, J = 8.6 Hz),6.89 (1H, dt, J = 2.8, 8.4 Hz), 7.04 (1H, s), 7.28-7.38 (3H, m), 7.54(1H, s), 7.87 (1H, d, J = 2.1 Hz) 109 1.24-2.03 (4H, m), 2.34 (3H, s),2.42-2.57 (2H, m), 2.64-2.72 (1H, m), 3.71 (3H, s), 3.78 (1H, d, J =14.3 Hz), 4.09-4.24 (2H, m), 5.60 (1H, d, J = 14.3 Hz), 5.88 (1H, s),6.50-6.59 (2H, m), 6.81-6.87 (2H, m), 7.06 (1H, d, J = 7.7 Hz), 7.17(1H, s), 7.37-7.42 (1H, m), 8.10 (1H, d, J = 4.2 Hz) 110 (DMSO-d6)1.20-1.34 (1H, m), 1.43-1.54 (1H, m), 1.68-1.77 (2H, m), 2.15 (3H, s),2.20-2.31 (2H, m), 2.31 (3H, s), 2.39-2.48 (1H, m), 3.20 (1H, d, J =12.9 Hz), 3.31-3.38 (1H, m), 3.68 (3H, s), 3.70 (1H, d, J = 14.4 Hz),5.39 (1H, d, J = 14.4 Hz), 6.83-6.88 (2H, m), 7.08 (1H, s), 7.14 (2H, d,J = 7.6 Hz), 7.44 (1H, d, J = 7.1 Hz), 8.00 (1H, dd, J = 1.4, 4.9 Hz),8.31 (1H, s) 111 (DMSO-d6): 1.21-1.27 (2H, m), 1.51-1.63 (1H, m),1.63-1.70 (1H, m), 2.16 (3H, s), 2.31 (3H, s), 2.34-2.47 (2H, m),2.50-2.58 (1H, m), 3.68 (3H, s), 3.69 (1H, d, J = 14.4 Hz), 4.09 (1H, d,J = 13.1 Hz), 4.23 (1H, d, J = 13.1 Hz), 5.35 (1H, d, J = 14.4 Hz), 6.40(1H, d, J = 5.0 Hz), 6.56 (1H, s), 6.83 (1H, dd, J = 1.4, 8.0 Hz), 7.05(1H, s), 7.10 (1H, s), 7.14 (1H, d, J = 1.4 Hz), 7.89 (1H, d, J = 5.0Hz), 8.30 (1H, s) 112 (DMSO-d6) 1.18-1.31 (2H, m), 1.52-1.60 (1H, m),1.62-1.70 (1H, m), 2.09 (3H, s), 2.30 (3H, s), 2.36-2.42 (2H, m),2.50-2.58 (1H, m), 3.68 (3H, s), 3.72 (1H, d, J = 14.5 Hz), 4.00-4.05(1H, m), 4.16 (1H, d, J = 13.2 Hz), 5.35 (1H, d, J = 14.5 Hz), 6.66 (1H,d, J = 8.6 Hz), 6.83 (1H, dd, J = 1.3, 8.0 Hz), 7.05 (1H, s), 7.14 (2H,d, J = 8.0 Hz), 7.3 (1H, dd, J = 2.4, 8.6 Hz), 7.86 (1H, d, J = 2.3 Hz),8.31 (1H, s) 113 (DMSO-d6) 1.21-1.33 (2H, m), 1.52-1.64 (1H, m),1.68-1.73 (1H, m), 2.31 (3H, s), 2.32-2.47 (2H, m), 2.52-2.60 (1H, m),3.67 (3H, s), 3.70 (3H, s), 4.07 (1H, d, J = 13.3 Hz), 4.20 (1H, d, J =13.3 Hz), 5.35 (1H, d, J = 14.5 Hz), 5.95 (1H, d, J = 7.8 Hz), 6.22 (1H,d, J = 8.1 Hz), 6.83 (1H, dd, J = 1.4, 8.0 Hz), 7.06 (1H, s), 7.13-7.18(2H, m), 7.37 (1H, t, J = 8.0 Hz), 8.31 (1H, s) 114 1.27-1.92 (4H, m),2.20 (3H, s), 2.24 (3H, s), 2.32-2.47 (2H, m), 2.58-2.67 (1H, m), 3.78(1H, d, J = 14.6 Hz), 4.05 (1H, d, J = 13.0 Hz), 4.18 (1H, d, J = 13.0Hz), 5.19 (1H, d, J = 16.6 Hz), 5.37 (1H, d, J = 16.6 Hz), 5.60 (1H, s),5.61 (1H, d, J = 14.6 Hz), 6.26 (1H, s), 6.38-6.40 (2H, m), 6.78 (1H, d,J = 7.8 Hz), 7.00 (1H, d, J = 7.8 Hz), 7.14-7.17 (2H, m), 7.32-7.38 (4H,m), 7.97 (1H, d, J = 5.7 Hz) 115 1.38-1.99 (4H, m), 2.37-2.73 (3H, m),3.70 (3H, s), 3.79 (1H, d, J = 14.6 Hz), 4.06-4.25 (2H, m), 5.59 (1H, d,J = 14.6 Hz), 6.11 (1H, s), 6.51-6.58 (2H, m), 7.02 (2H, d, J = 8.0 Hz),7.12 (1H, d, J = 8.0 Hz), 7.17 (1H, s), 7.39 (1H, t, J = 7.2 Hz), 8.10(1H, d, J = 3.7 Hz) 116 (DMSO-d6) 1.23-1.32 (1H, m), 1.42-1.55 (1H, m),1.74-1.83 (2H, m), 2.15 (3H, s), 2.27-2.32 (2H, m), 2.42-2.48 (1H, m),3.20 (1H, d, J = 12.8 Hz), 3.36 (1H, d, J = 12.8 Hz), 3.68 (3H, s), 3.74(1H, d, J = 14.5 Hz), 5.38 (1H, d, J = 14.5 Hz), 6.85 (1H, dd, J = 4.9,7.3 Hz), 7.05 (1H, dd, J = 2.4, 8.4 Hz), 7.11 (1H, s), 7.32 (1H, d, J =8.4 Hz), 7.43 (2H, d, J = 2.4 Hz), 8.01 (1H, dd, J = 1.4, 4.8 Hz), 8.57(1H, s) 117 (DMSO-d6): 1.21-1.27 (2H, m), 1.51-1.63 (1H, m), 1.66-1.71(1H, m), 2.16 (3H, s), 2.37-2.46 (2H, m), 2.54-2.62 (1H, m), 3.68 (3H,s), 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6.29(1H, dd, J = 2.2, 7.8 Hz), 6.33-6.35 (1H, m), 6.42 (1H, dd, J = 2.2, 8.1Hz), 7.00-7.05 (2H, m), 7.10 (1H, s), 7.32 (1H, d, J = 7.8 Hz), 7.43(1H, d, J = 2.2 Hz), 8.57 (1H, s). 138 (DMSO-d6) 1.27 (1H, dd, J = 2.5,12.9 Hz), 1.37-1.48 (1H, m), 1.72-1.77 (2H, m), 2.16 (1H, dt, J = 2.5,12.3 Hz), 2.20-2.27 (1H, m), 2.30-2.39 (1H, m), 3.31 (1H, d, J = 11.7Hz), 3.45 (1H, d, J = 11.7 Hz), 3.64 (3H, s), 3.68 (3H, s), 3.74 (1H, d,J = 14.3 Hz), 5.37 (1H, d, J = 14.3 Hz), 6.74 (2H, d, J = 9.2 Hz), 6.79(2H, d, J = 9.2 Hz), 7.04 (1H, dd, J = 2.2, 8.4 Hz), 7.09 (1H, s), 7.32(1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 2.2 Hz), 8.57 (1H, s). 139(DMSO-d6) 1.09 (3H, t, J = 7.9 Hz), 1.26 (1H, dd, J = 2.5, 12.5 Hz),1.35-1.45 (1H, m), 1.70-1.76 (2H, m), 2.18-2.31 (2H, m), 2.36-2.47 (1H,m), 2.45 (2H, q, J = 7.9 Hz), 3.43 (1H, d, J = 12.4 Hz), 3.57 (1H, d, J= 12.4 Hz), 3.68 (3H, s), 3.73 (1H, d, J = 14.3 Hz), 5.36 (1H, d, J =14.3 Hz), 6.75 (2H, d, J = 8.5 Hz), 6.98 (2H, d, J = 8.5 Hz), 7.04 (1H,dd, J = 2.2, 8.5 Hz), 7.09 (1H, s), 7.32 (1H, d, J = 8.5 Hz), 7.43 (1H,d, J = 2.2 Hz), 8.56 (1H, s). 140 (DMSO-d6) 1.25-1.40 (2H, m), 1.63-1.75(2H, m), 2.37-2.45 (2H, m), 2.61-2.68 (1H, m), 3.68 (3H, s), 3.70-3.79(2H, m), 3.83 (1H, d, J = 13.1 Hz), 5.36 (1H, d, J = 14.5 Hz), 6.96 (2H,d, J = 8.8 Hz), 7.05 (1H, dd, J = 2.4, 8.4 Hz), 7.09 (1H, s), 7.33 (1H,d, J = 8.4 Hz), 7.41 (1H, s), 7.43-7.45 (2H, m), 8.57 (1H, s). 141(DMSO-d6) 1.23-1.32 (1H, m), 1.37-1.46 (1H, m), 1.66-1.78 (2H, m),2.14-2.29 (2H, m), 2.30 (6H, s), 2.36-2.48 (1H, m), 3.47 (1H, d, J =12.4 Hz), 3.62 (1H, d, J = 12.4 Hz), 3.67 (3H, s), 3.68 (1H, d, J = 14.5Hz), 5.37 (1H, d, J = 14.5 Hz), 6.82 (1H, dd, J = 1.3, 8.1 Hz), 6.99(1H, d, J = 8.6 Hz), 7.07 (1H, s), 7.13 (1H, d, J = 2.8 Hz), 7.15 (2H,d, J = 1.5 Hz), 8.04 (1H, d, J = 2.8 Hz), 8.32 (1H, s) 142 (DMSO-d6)1.23-1.30 (1H, m), 1.33-1.45 (1H, m), 1.70-1.77 (2H, m), 2.23-2.35 (2H,m), 2.30 (3H, s), 2.41-2.49 (1H, m), 3.47 (1H, d, J = 12.4 Hz), 3.61(1H, d, J = 12.4 Hz), 3.68 (3H, s), 3.73 (1H, d, J = 14.5 Hz), 5.35 (1H,d, J = 14.5 Hz), 6.99 (1H, d, J = 8.5 Hz), 7.04 (1H, dd, J = 2.3, 8.4Hz), 7.10 (1H, s), 7.14 (1H, dd, J = 3.0, 8.6 Hz), 7.33 (1H, d, J = 8.4Hz), 7.43 (1H, d, J = 2.3 Hz), 8.05 (1H, d, J = 3.0 Hz), 8.58 (1H, s)143 1.35-1.60 (1H, m), 1.60-2.10 (3H, m), 2.45-2.85 (3H, m), 4.13 (1H,d, J = 16.1 Hz), 4.55-4.85 (4H, m), 5.26 (1H, d, J = 13.6 Hz), 5.85-6.15(3H, m), 6.42 (1H, t, J = 4.7 Hz), 6.58 (1H, m), 7.20-7.55 (4H, m), 8.25(1H, d, J = 4.7 Hz) 144 1.40-1.55 (1H, m), 1.71-2.11 (3H, m), 2.42-2.75(2H, m), 4.06-4.35 (3H, m), 4.71 (1H, d, J = 16.2 Hz), 5.26 (1H, d, J =16.2 Hz), 5.90-6.02 (2H, m), 6.05 (1H, s), 6.50-6.62 (3H, m), 7.27-7.30(2H, m), 7.31-7.47 (4H, m), 8.12 (1H, d, J = 3.9 Hz) 145 (MeOH, D3)1.25-1.35 (1H, m), 1.50-1.54 (1H, m), 1.75-1.91 (4H, m), 2.15 (3H, s),2.46-2.63 (2H, m), 4.04-4.19 (3H, m), 4.90 (1H, d, J = 14.1 Hz), 5.18(1H, d, J = 14.1 Hz), 5.77 (1H, d, J = 16.1 Hz), 5.90-5.97 (2H, m),6.65-6.66 (1H, m), 6.72 (1H, d, J = 8.7 Hz), 7.42-7.54 (4H, m), 7.86(1H, brs). 146 1.48-1.58 (1H, m), 1.86-2.21 (3H, m), 2.37-2.66 (3H, m),3.53-3.75 (2H, m), 4.09-4.18 (1H, m), 4.65-4.75 (1H, m), 5.21-5.32 (1H,m), 5.98 (2H, t, J = 7.4 Hz), 6.06 (1H, t, J = 3.0 Hz), 6.59 (1H, t, J =1.9 Hz), 7.08-7.15 (2H, m), 7.26-7.32 (1H, m), 7.33-7.49 (3H, m), 8.04(1H, t, J = 2.7 Hz), 8.22 (1H, s) 147 1.35-1.48 (1H, m), 1.49-1.61 (1H,m), 1.77-2.18 (4H, m), 2.66-2.80 (1H, m), 2.95-3.22 (3H, m), 3.90-4.10(2H, m), 4.16 (1H, d, J = 8.1 Hz), 4.74, (1H, d, J = 8.1 Hz), 5.22 (1H,d, J = 8.1 Hz), 5.85-6.00 (1H, m), 6.08 (1H, s), 6.55-6.63 (1H, m),6.66-6.82 (1H, m), 7.28-7.32 (1H, m), 7.33-7.50 (3H, m), 8.02-8.20 (1H,m) 148 1.43-1.58 (1H, m), 1.71-2.07 (4H, m), 2.50-2.81 (3H, m),4.05-4.39 (3H, m), 4.71 (1H, d, J = 13.9 Hz), 5.25 (1H, d, J = 13.9 Hz),5.91-6.00 (2H, m), 6.04 (1H, t, J = 3.0 Hz), 6.58 (1H, s), 7.25-7.32(1H, m), 7.33-7.47 (2H, m), 7.77 (1H, d, J = 2.7 Hz), 7.96-8.01 (1H, m),8.07 (1H, s) 149 1.42-1.58 (2H, m), 1.79-2.22 (3H, m), 2.32-2.61 (3H,m), 3.52-3.73 (2H, m), 4.13 (1H, d, J = 16 Hz), 4.71 (1H, d, J = 13.9Hz), 5.26 (1H, d, J = 12.9 Hz), 5.88-6.11 (3H, m), 6.58 (1H, s),6.75-6.90 (3H, m), 7.12-7.50 (5H, m) 150 1.35-1.55 (1H, m), 1.60-2.15(3H, m), 2.40-2.80 (3H, m), 4.00-4.40 (2H, m), 4.13 (1H, d, J = 16.3Hz), 4.65 (1H, d, J = 14.1 Hz), 5.22 (1H, d, J = 14.1 Hz), 5.87-6.02(2H, m), 6.06 (1H, t, J = 3.2 Hz), 6.51-6.68 (3H, m), 7.04-7.22 (2H, m),7.22-7.34 (1H, m), 7.37-7.50 (1H, m), 8.09-8.20 (1H, m). 151 1.15-1.37(1H, m), 1.40-1.70 (2H, m), 1.75-2.20 (3H, m), 2.28-2.62 (2H, m),4.50-4.80 (2H, m), 4.13 (1H, d, J = 16.1 Hz), 4.65 (1H, d, J = 13.9 Hz),5.23 (1H, d, J = 13.9 Hz), 5.87-6.02 (2H, m), 6.06 (1H, t, J = 3.2 Hz),6.53-6.64 (1H, m), 6.76-6.98 (1H, m), 6.85 (2H, d, J = 8.7 Hz),7.03-7.40 (4H, m). 152 1.48-1.55 (2H, m), 1.79-1.99 (3H, m), 2.38 (3H,s), 2.51-2.67 (3H, m), 4.11 (1H, d, J = 15.8 Hz), 4.23-4.29 (2H, m),4.63 (1H, d, J = 13.9 Hz), 5.22 (1H, d, J = 13.6 Hz), 5.91-5.97 (2H, m),6.03 (1H, s), 6.52-6.60 (3H, m), 7.13-7.24 (2H, m), 7.42 (1H, t, J = 7.2Hz), 8.12 (1H, d, J = 4.2 Hz). 153 1.80-2.10 (4H, m), 2.37 (3H, s),2.41-2.52 (4H, m), 3.59-3.69 (2H, m), 4.11 (1H, d, J = 16.6 Hz), 4.63(1H, d, J = 13.9 Hz), 5.23 (1H, d, J = 13.9 Hz), 5.95-5.99 (2H, m), 6.04(1H, t, J = 3.2 Hz), 6.56 (1H, s), 6.77-6.86 (3H, m), 7.13-7.24 (4H, m).154 1.40-1.60 (1H, m), 1.78-2.28 (3H, m), 2.30-2.60 (3H, m), 3.35 (1H,d, J = 11.6 Hz), 3.45 (1H, d, J = 11.6 Hz), 4.14 (1H, d, J = 15.8 Hz),4.70 (1H, d, J = 15.8 Hz), 5.17-5.36 (1H, m), 5.90-6.12 (3H, m), 6.58(1H, m), 6.76-7.10 (4H, m), 7.22-7.52 (4H, m). 155 1.40-1.70 (1H, m),1.70-2.20 (3H, m), 2.25-3.65 (3H, m), 3.57 (1H, d, J = 12.3 Hz), 3.68(1H, d, J = 12.4 Hz), 4.15 (1H, d, J = 16.1 Hz), 4.71 (1H, d, J = 12.4Hz), 5.26 (1H, d, J = 12.4 Hz), 5.86-6.14 (2H, m), 6.06 (1H, t, J = 3.0Hz), 6.40-6.60 (4H, m), 7.13 (1H, quartet, J = 7.9 Hz), 7.22-7.52 (4H,m). 156 1.40-1.70 (1H, m), 1.75-2.20 (3H, m), 2.22-2.55 (3H, m), 3.44(1H, d, J = 11.4 Hz), 3.54 (1H, d, J = 11.4 Hz), 4.14 (1H, d, J = 16.1Hz), 4.71 (1H, d, J = 13.9 Hz), 5.26 (1H, d, J = 13.9 Hz), 5.90-6.10(2H, m), 6.06 (1H, t, J = 3.0 Hz), 6.58 (1H, m), 6.72-6.98 (4H, m),7.22-7.50 (4H, m). 157 1.40-1.62 (1H, m),, 1.75-1.85 (1H, m), 1.85-2.58(5H, m), 3.29 (1H, d, J = 10.6 Hz), 3.38 (1H, d, J = 10.6 Hz), 4.15 (1H,d, J = 16.6 Hz), 4.71 (1H, d, J = 13.9 Hz), 5.28 (1H, d, J = 13.9 Hz),5.90-6.12 (3H, m), 6.58 (1H, s), 6.82-6.98 (2H, m), 7.07-7.20 (1H, m),7.22-7.52 (5H, m). 158 1.38-1.70 (1H, m), 1.75-2.20 (3H, m), 2.25-2.60(3H, m), 3.51 (1H, d, J = 11.4 Hz), 3.62 (1H, d, J = 11.4 Hz), 4.14 (1H,d, J = 16.3 Hz), 4.71 (1H, d, J = 13.9 Hz), 5.26 (1H, d, J = 13.9 Hz),5.90-6.14 (2H, m), 6.06 (1H, t, J = 3.0 Hz), 6.58 (1H, s), 6.76 (2H, d,J = 8.9 Hz), 7.14 (2H, d, J = 8.9 Hz), 7.22-7.52 (4H, m). 159 1.40-1.60(1H, m), 1.80-2.55 (6H, m), 2.27 (3H, s), 3.02 (1H, d, J = 10.6 Hz),3.12 (1H, d, J = 10.6 Hz), 4.16 (1H, d, J = 15.6 Hz), 4.71 (1H, d, J =13.9 Hz), 5.28 (1H, d, J = 13.9 Hz), 5.92-6.15 (3H, m), 6.59 (1H, s),6.80-7.03 (2H, m), 7.03-7.22 (2H, m), 7.22-7.52 (4H, m). 160 1.56 (2H,m), 1.90-2.20 (4H, m), 2.30 (3H, s), 2.36-2.45 (2H, m), 3.59-3.68 (2H,m), 4.13 (1H, d, J = 16.6 Hz), 4.73 (1H, d, J = 13.6 Hz), 5.29 (1H, d, J= 13.6 Hz), 5.97 (2H, m), 6.05 (1H, t, J = 3.2 Hz), 6.58-6.67 (4H, m),7.10 (1H, t, J = 7.9 Hz), 7.25-7.42 (3H, m). 161 1.53 (1H, m), 1.90-2.10(4H, m), 2.28 (3H, s), 2.34-2.45 (3H, m), 3.53-3.61 (2H, m), 4.14 (1H,d, J = 16.1 Hz), 4.70 (1H, d, J = 13.9 Hz), 5.27 (1H, d, J = 13.9 Hz),5.97-6.01 (2H, m), 6.05 (1H, t, J = 3.2 Hz), 6.58 (1H, s), 6.76 (2H, d,J = 8.4 Hz), 7.03 (2H, d, J = 8.2 Hz), 7.27-7.30 (1H, m), 7.37-7.42 (2H,m). 162 1.40-1.60 (1H, m), 1.78-1.94 (1H, m), 1.94-2.50 (5H, m),3.30-3.60 (2H, m), 3.84 (3H, s), 4.14 (1H, d, J = 16.1 Hz), 4.70 (1H, d,J = 13.6 Hz), 5.28 (1H, d, J = 13.6 Hz), 5.90-6.12 (3H, m), 6.58 (1H,m), 6.74-7.04 (4H, m), 7.20-7.50 (4H, m). 163 1.42-1.65 (1H, m),1.75-2.22 (3H, m), 2.30-2.60 (3H, m), 3.57 (1H, d, J = 12.6 Hz), 3.68(1H, d, J = 12.6 Hz), 3.75 (3H, s), 4.14 (1H, d, J = 16.1 Hz), 4.70 (1H,d, J = 13.6 Hz), 5.26 (1H, d, J = 13.6 Hz), 5.90-6.14 (2H, m), 6.05 (1H,t, J = 3.1 Hz), 6.31-6.42 (2H, m), 6.42-6.52 (1H, m), 6.58 (1H, m),7.05-7.18 (1H, m), 7.20-7.52 (4H, m). 164 (CD₃OD) 1.47-1.65 (1H, m),1.70-2.12 (3H, m), 2.15-2.52 (3H, m), 3.35 (1H, d, J = 11.4 Hz), 3.47(1H, d, J = 11.4 Hz), 3.70 (3H, s), 4.13 (1H, d, J = 16.1 Hz), 4.82-5.00(1H, m), 5.18 (1H, d, J = 14.1 Hz), 5.82 (1H, d, J = 16.1 Hz), 5.88-6.06(2H, m), 6.65 (1H, m), 6.78 (2H, d, J = 9.2 Hz), 6.87 (2H, d, J = 9.2Hz), 7.34-7.60 (4H, m). 165 1.17 (3H, t J = 7.4 Hz), 1.40-1.59 (1H, m),1.80-2.20 (3H, m), 2.27-2.43 (3H, m), 2.44-2.61 (2H, m), 3.43-3.72 (2H,m), 4.14 (1H, d, J = 15.8 Hz), 4.70 (1H, d, J = 14.4 Hz), 5.27 (1H, d, J= 14.4 Hz), 5.92-6.03 (2H, m), 6.04-6.11 (1H, m), 6.58 (1H, s), 6.78(2H, d J = 8.4 Hz), 7.04 (2H, d J = 8.4 Hz), 7.26-7.31 (1H, m),7.32-7.50 (3H, m) 166 0.89 (3H, t, J = 7.4 Hz), 1.43-1.67 (3H, m),1.73-2.20 (3H, m), 2.27-2.56 (5H, m), 3.45-3.70 (1H, m), 4.14 (1H, d, J= 14.8 Hz), 4.71 (1H, d, J = 15.1 Hz), 5.27 (1H, d, J = 14.8 Hz),5.90-6.00 (2H, m), 6.01-6.11 (1H, m), 6.58 (1H, s), 6.78 (2H, d, J = 8.5Hz), 7.00 (2H, d, J = 8.5 Hz), 7.26-7.31 (2H, m), 7.32-7.47 (3H, m) 1671.17 (6H, d, J = 6.9 Hz), 1.40-1.60 (1H, m), 1.78-2.20 (3H, m),2.27-2.53 (3H, m), 2.71-2.86 (1H, m), 3.42-3.70 (2H, m), 4.12 (1H, d, J= 16.8 Hz), 4.69 (1H, d, J = 13.9 Hz), 5.25 (1H, d, J = 13.9 Hz),5.90-5.98 (2H, m), 5.99-6.08 (1H, m), 6.57 (1H, s), 6.77 (2H, d, J = 8.4Hz), 7.05 (2H, d, J = 8.4 Hz), 7.26-7.30 (1H, m), 7.31-7.47 (3H, m) 168(DMSO-d6) 1.52-2.07 (4H, m), 2.39-2.44 (2H, m), 3.67-3.80 (2H, m), 4.07(1H, d, J = 15.8 Hz), 5.10 (1H, d, J = 15.1 Hz), 5.80 (1H, d, J = 16.1Hz), 5.90 (2H, d, J = 11.4 Hz), 6.74 (1H, s), 6.87-7.62 (15H, m). 169(DMSO-d6) 1.43-1.89 (4H, m), 2.60-2.71 (2H, m), 3.71-3.92 (2H, m), 4.06(1H, d, J = 16.3 Hz), 5.07 (2H, q, J = 13.1 Hz), 5.75 (1H, d, J = 16.3Hz), 5.87 (1H, s), 5.92 (1H, t, J = 3.2 Hz), 6.74 (1H, t, J = 2.0 Hz),6.99 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.48-7.53 (2H, m),7.54-7.65 (2H, m) 170 (DMSO-d6) 1.51-1.63 (1H, m), 1.70-2.00 (3H, m),2.30-2.61 (4H, m), 3.41-3.52 (1H, m), 4.08 (1H, d, J = 16.3 Hz), 5.12(2H, q, J = 13.1 Hz), 5.77 (1H, d, J = 16.3 Hz), 5.91 (2H, d, J = 9.4Hz), 6.74 (1H, s), 7.05 (2H, t, J = 8.2 Hz), 7.40 (1H, d, J = 7.4 Hz),7.43-7.62 (4H, m), 7.65 (1H, d, J = 7.4 Hz) 171 (DMSO-d6) d 1.34-1.57(4H, m), 2.22-2.25 (4H, m), 3.40-3.51 (2H, m), 3.79 (1H, d, J = 15.1Hz), 4.78-4.91 (2H, m), 5.47 (1H, d, J = 16.1 Hz), 5.64 (2H, d, J = 11.6Hz), 6.46 (1H, s), 6.83-7.26 (7H, m). 172 1.50-1.60 (1H, m), 1.75-2.15(6H, m), 2.63-2.45 (3H, m), 3.62-3.67 (2H, m), 3.74 (2H, brs), 4.14 (1H,d, J = 15.8 Hz), 4.71 (1H, d, J = 13.9 Hz), (1H, d, J = 13.9 Hz), 5.97(2H, brs), 6.05 (1H, t, J = 3.5 Hz), 6.58 (1H, s), 6.82 (2H, d, J = 8.7Hz), 7.16 (2H, d, J = 8.4 Hz), 7.25-7.30 (1H, m), 7.40-7.42 (2H, m). 173(DMSO-d6) 1.39-1.48 (1H, m), 1.61-1.92 (3H, m), 2.29-2.41 (1H, m),2.42-2.58 (3H, m), 2.99-3.22 (2H, m), 4.07 (1H, d, J = 16.8 Hz), 5.10(2H, q, J = 13.9 Hz), 5.80 (1H, d, J = 16.8 Hz), 5.90-5.99 (2H, m), 6.72(1H, t, J = 2.1 Hz), 7.04-7.12 (1H, m), 7.24 (1H, d, 7.9 Hz), 7.39-7.62(4H, m), 7.76 (1H, dd, J = 1.5 Hz, 8.2 Hz) 174 1.52-1.88 (4H, m),2.50-2.70 (4H, m), 3.82-3.87 (2H, m), 4.06 (1H, d, J = 15.8 Hz),4.90-5.18 (2H, m), 5.76 (1H, d, J = 16.1 Hz), 5.90-5.93 (2H, m), 6.73(1H, s), 7.42-7.58 (7H, m). 176 1.89-2.03 (4H, m), 2.36-2.43 (3H, m),3.02-3.16 (2H, m), 3.95 (2H, brs), 4.10-4.18 (1H, m), 4.71 (1H, d, J =13.8 Hz), 5.27 (1H, d, J = 13.8 Hz), 5.98-6.06 (3H, m), 6.58-6.70 (4H,m), 6.82-6.88 (2H, m), 7.25-7.44 (3H, m) 178 1.48-1.52 (1H, m),1.89-1.99 (3H, m), 2.36-2.49 (3H, m), 2.98-3.11 (4H, m), 3.93 (2H, s),4.13 (1H, d, J = 16.1 Hz), 4.69 (1H, d, =13.6 Hz), 5.26 (1H, d, J = 13.6Hz), 5.93-5.97 (2H, m), 6.05 (1H, t, J = 3.0 Hz), 6.57 (1H, s),7.04-7.43 (8H, m)

TABLE 18 Names of Examples Example Name 6(2-Methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone 7(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone 8(2-Methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 9(2-Morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 10(3′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone 11(4′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone 12(5′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone 13(9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 14(9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone15(9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone16(9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone17(2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 18(2-Ethyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 19(2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 20(9-Methyl-2-propyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 21(9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 22(9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 23(9-Methyl-2-propyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 24(2-Cyclopropyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 25(2-Cyclopropyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone26 (2-Butyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 27(2-Butyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 28(2-Isobutyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 29(2-Isobutyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 30[9-Methyl-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(5′-methyl-3,4,5,6-tetrahydro-2[1,2′]bipyridinyl-4-yl)-methanone 31(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 32(9-Methyl-2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone33(4′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone 34(5′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone 35(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 36 4-(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile 37(3′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone 38(4′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone 39(5′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone 40(3′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone 41(4′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone 42(5′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone 43(9-Methyl-2-pyrrolidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone44 (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 45(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 46(9-Chloro-2-ethyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 47(9-Chloro-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 48(9-Chloro-2-cyclopropyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 49(9-Chloro-2-cyclohexyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 50(9-Chloro-2-piperidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 51[9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 52[9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 53(9-Chloro-2-phenyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 54[9-Chloro-2-(2-fluoro-phenyl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 55 [9-Chloro-2-(3-fluoro-phenyl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 56(2-Benzyl-9-chloro-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 57(9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 58(9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone59(9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone60(6′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone 61(2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 62(9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 63(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone64(6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone 65(6′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone 66(6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone 67(9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone68(9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 69(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone70(9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone71(9-Methyl-2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone72(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone 73(9-Chloro-2-ethyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone 74(9-Chloro-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone 75(9-Chloro-2-cyclopropyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone 76(9-Chloro-2-cyclohexyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone 77(9-Chloro-2-piperidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone 78[9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(1-phenyl-piperidin-4-yl)-methanone 79(9-Chloro-2-phenyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone 80[9-Chloro-2-(2-fluoro-phenyl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(1-phenyl-piperidin-4-yl)-methanone 81[9-Chloro-2-(3-fluoro-phenyl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(1-phenyl-piperidin-4-yl)-methanone 82(2-Benzyl-9-chloro-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone 83(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone 84(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(3-fluoro-phenyl)-piperidin-4-yl]-methanone 85(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-fluoro-phenyl)-piperidin-4-yl]-methanone 86(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(2-chloro-phenyl)-piperidin-4-yl]-methanone 87(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(3-chloro-phenyl)-piperidin-4-yl]-methanone 88(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-chloro-phenyl)-piperidin-4-yl]-methanone 89(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-o-tolyl-piperidin-4-yl)-methanone 90(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-m-tolyl-piperidin-4-yl)-methanone 91(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-p-tolyl-piperidin-4-yl)-methanone 92(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(2-methoxy-phenyl)-piperidin-4-yl]-methanone 93(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone 94(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone 95(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone 96(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-propyl-phenyl)-piperidin-4-yl]-methanone 97(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-isopropyl-phenyl)-piperidin-4-yl]-methanone 98(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone 99(3-Cyclohexyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl]-methanone 100(6-Fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone 101(3-Ethyl-6-fluoro-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl]-methanone 102(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone 103(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone 104(6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone 105(6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-methanone 106(3-Methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 107(3-Ethyl-6-fluoro-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 108(3-tert-Butyl-6-fluoro-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone109 (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 110(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 111(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 112(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 113(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 114(3-Benzyl-6-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone115(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 116(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone117(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone118(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone119(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone120(6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 121(6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 122(6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 123(6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone124(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 125(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone126(6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 127(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone 128(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-m-tolyl-piperidin-4-yl)-methanone 129(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-p-tolyl-piperidin-4-yl)-methanone 130(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone 131(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone 132(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone 133(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone 134(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone 135(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-m-tolyl-piperidin-4-yl)-methanone 136(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-p-tolyl-piperidin-4-yl)-methanone 137(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone 138(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone 139(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone 140(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone 141(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone 142(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone143(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone 144(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 145(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 146(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone 147(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methanone 148(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-pyrazin-2-yl-piperidin-4-yl)-methanone 149(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone 150(7-Fluoro-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 151(7-Fluoro-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone 152(7-Methyl-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone 153(7-Methyl-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone 154(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone 155(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-fluoro-phenyl)-piperidin-4-yl]-methanone 156(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-fluoro-phenyl)-piperidin-4-yl]-methanone 157(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-chloro-phenyl)-piperidin-4-yl]-methanone 158(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-chloro-phenyl)-piperidin-4-yl]-methanone 159(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-o-tolyl-piperidin-4-yl)-methanone 160(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-m-tolyl-piperidin-4-yl)-methanone 161(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-p-tolyl-piperidin-4-yl)-methanone 162(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-methoxy-phenyl)-piperidin-4-yl]-methanone 163(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone 164(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone 165(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone 166(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-propyl-phenyl)-piperidin-4-yl]-methanone 167(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-isopropyl-phenyl)-piperidin-4-yl]-methanone 168(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-biphenyl-3-yl-piperidin-4-yl)-methanone 169(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone 1703-[4-(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-piperidin-1-yl]-benzonitrile 1714-[4-(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-piperidin-1-yl]-benzonitrile 172(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-nitro-phenyl)-piperidin-4-yl]-methanone 173(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-nitro-phenyl)-piperidin-4-yl]-methanone 174(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-nitro-phenyl)-piperidin-4-yl]-methanone 176[1-(4-Amino-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone 178[1-(4-Aminomethyl-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone

Biological Methods

The primary assay which may be used to determine the ability of thecompounds of formula (1) to inhibit the vasopressin V_(1a) receptor isan in vitro functional calcium mobilisation assay (FLIPR) that measuresantagonist activity at a cloned human V_(1a) receptor. The assay isdescribed below.

The antagonist activity of compounds of formula (1) were determined in aCalcium (Ca2+) mobilisation assay using whole cells (human brainastrocytoma 1321N1 cells, ex Perkin Elmer) genetically modified tostably express a cloned human V_(1a) receptor. Dose response curves weredetermined by displacement of a single concentration of agonist (250 pMAVP, ex Sigma) with increasing concentrations of compound. A pIC50 valueis determined by non-linear regression to a 4-parameter logisticequation and a functional pKi (fpKi) derived using Equation 1.

$\begin{matrix}{{{Modification}\mspace{14mu} {of}\mspace{14mu} {Cheng}\text{-}{Prusoff}\mspace{14mu} {to}\mspace{14mu} {derive}\mspace{14mu} {fpKi}}{{{Functional}\mspace{14mu} {pKi}} = {{Log}\left\lbrack \frac{{IC}_{50}}{\left\lbrack \frac{A}{A_{50}} \right\rbrack + 1} \right\rbrack}}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

where A=agonist single conc, and A50=the agonist EC₅₀.

Data acquired from this assays are shown in the table below:

TABLE 19 (In vitro activity) Example Mean fpKi (Human V1a) 1 9.01 2 8.843 9.01 4 8.83 5 8.75 6 6.04 7 7.31 8 6.82 9 7.74 10 8.30 11 8.43 12 8.6713 8.10 14 8.60 15 8.71 16 8.53 17 8.30 18 8.64 19 8.63 20 7.91 21 8.3522 8.69 23 8.67 24 8.06 25 8.82 26 7.74 27 8.35 28 7.87 29 8.57 30 8.7531 8.42 32 8.80 33 9.01 34 8.57 35 8.15 36 7.01 37 8.36 38 8.65 39 8.7040 8.90 41 8.63 42 8.25 43 8.12 44 7.90 45 8.20 46 7.87 47 7.93 48 7.9949 7.63 50 7.61 51 7.76 52 8.96 53 7.19 54 7.12 55 7.01 56 7.10 57 8.6058 9.19 59 9.10 60 7.89 61 8.13 62 8.13 63 8.73 64 8.20 65 8.12 66 7.5167 8.87 68 8.72 69 7.86 70 8.18 71 7.78 72 8.04 73 8.21 74 7.82 75 7.9676 7.55 77 7.74 78 8.06 79 7.11 80 7.09 81 7.03 82 7.37 83 7.58 84 7.4285 7.96 86 7.50 87 7.16 88 8.21 89 7.59 90 8.02 91 8.90 92 7.64 93 8.6094 7.79 95 8.50 96 7.87 97 7.65 98 6.85 99 7.45 100 6.84 101 6.24 1026.82 103 7.12 104 7.85 105 7.86 106 7.90 107 8.72 108 8.27 109 7.89 1108.34 111 8.62 112 8.55 113 7.52 114 7.70 115 8.16 116 8.57 117 8.70 1188.76 119 7.72 120 9.04 121 9.37 122 9.22 123 8.70 124 8.02 125 8.23 1268.92 127 8.70 128 8.88 129 9.49 230 8.61 131 8.51 132 9.13 133 8.27 1348.76 135 8.89 136 9.21 137 8.75 138 8.58 139 9.04 140 8.07 141 8.29 1428.54 143 6.93 144 8.50 145 7.82 146 7.50 147 5.83 148 7.55 149 9.23 1508.72 151 9.10 152 9.20 153 9.63 154 8.83 155 8.34 156 8.84 157 8.12 1588.32 159 7.98 160 8.50 161 8.95 162 8.50 163 8.25 164 7.85 165 8.81 1668.41 167 8.44 168 6.82 169 7.51 170 7.59 171 6.67 172 7.35 173 7.77 1746.79 175 8.40 176 8.60 177 7.54 178 7.01

1. A compound of formula (1):

wherein, G is a fused azepine selected from formula (2), (3), or (4),

wherein, R¹ is H, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-; R² is (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cyclo alkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-; R³ is H, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-; R⁴ is (C₁-C₁₀)alkyl, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-; R⁵ is H, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl- or heteroaryl(C₁-C₄)alkyl-; and A is phenyl or a 5- or 6-membered aromatic ring containing 1, 2 or 3 N atoms, wherein said phenyl or said 5- or 6-membered ring are optionally substituted with 1 to 3 substituents independently chosen from the group consisting of halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl-, heteroaryl(C₁-C₄)alkyl-, CF₃, CN, NO₂, OH, CO₂R^(d) and NR^(d)R^(e), wherein each alkyl may independently be optionally substituted with 1 or 2 substituents independently selected from (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, CO₂R^(p), halo and NR^(p)R^(q); each alkenyl may independently be optionally substituted with 1 or 2 substituents independently selected from (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, CO₂R^(r), halo and N^(r)R^(s); each alkoxy may independently be optionally be substituted with 1 or 2 substituents independently selected from (C₃-C₁₀)cycloalkyl, OH, CN, CF₃, CO₂R^(t), halo and NR^(t)R^(u); each cycloalkyl is independently a non-aromatic mono- or bicylic hydrocarbon ring, optionally fused to an aryl group, wherein said cycloalkyl ring may optionally contain up to 2 double bonds; and wherein, unless otherwise stated, said cycloalkyl may optionally be substituted with 1 or 2 substituents independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, CO₂R^(v), halo and NR^(v)R^(w); each heterocycloalkyl is independently a C-linked or N-linked non-aromatic, 3-10 membered mono- or bicyclic ring, wherein said heterocycloalkyl ring may contain 1, 2 or 3 ring members independently selected from N, NR^(x), S(O)_(y) and O; and said heterocycloalkyl ring may optionally contain 1 or 2 double bonds, and is optionally substituted on carbon with 1 or 2 substituents independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, halo, CO₂R^(x), NR^(x)R^(y) and aryl; aryl is a 6 or 10 membered aromatic mono- or bicyclic ring system; wherein, unless otherwise stated, each occurrence of aryl may be optionally substituted with up to 5 substituents independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, halo, CN, CO₂R^(a), CF₃ and NR^(a)R^(z); heteroaryl is a 5, 6, 9 or 10 membered aromatic mono- or bicyclic ring system, containing 1 or 2 N atoms and, optionally, an NR^(b) ring member, or one NR^(b) ring member and an S or an O atom, or one S atom, or one O atom; wherein, unless otherwise stated, said heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, halo, CN, CO₂R^(b), CF₃ and NR^(b)R^(c); wherein R^(p), R^(q), R^(r), R^(s), R^(t), R^(u), R^(v), R^(w), R^(x), R^(y), R^(a), R^(z), R^(b), R^(c), R^(d) and R^(e) are each independently selected from H and (C₁-C₆)alkyl; and y is 0, 1 or 2; or a pharmaceutically acceptable salt or solvate thereof.
 2. A compound according to claim 1, wherein A is a phenyl or a 6-membered aromatic ring containing 1, 2 or 3 N atoms and wherein said phenyl or said 6-membered ring are optionally substituted with 1 to 3 substituents independently chosen from the group consisting of halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cyclo alkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl-, heteroaryl(C₁-C₄)alkyl-, CF₃, CN, NO₂, OH, CO₂R^(d) and NR^(d)R^(e), wherein R^(d) and R^(e) are as previously defined.
 3. A compound according to claim 1, wherein A is selected from the group consisting of:

wherein each R⁷, R⁸ and R⁹ is independently selected from the group consisting of H, halo, (C₁-C₁₀)alkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl-, heteroaryl(C₁-C₄)alkyl-, CF₃, CN, NO₂, OH, CO₂R^(d) and NR^(d)R^(e), wherein R^(d) and R^(e) are each independently selected from H and (C₁-C₆)alkyl.
 4. A compound according to claim 3, wherein at least one of R⁷-R⁹ is H.
 5. A compound according to claim 1, wherein G is a fused azepine of general formula
 2.


6. A compound according to claim 5, wherein R¹ is H, halo or (C₁-C₆)alkyl.
 7. A compound according to claim 5 or claim 6, wherein R² is (C₁-C₆)alkyl, aryl, heterocycloalkyl or aryl(C₁-C₄)alkyl-.
 8. A compound according to claim 1, wherein G is a fused azepine of general formula
 3.


9. A compound according to claim 8, wherein R³ is H, halo or (C₁-C₆)alkyl.
 10. A compound according to claim 8 or claim 9, wherein R⁴ is (C₁-C₆)alkyl, aryl or aryl(C₁-C₄)alkyl-.
 11. A compound according to claim 1, wherein G is a fused azepine of general formula
 4.


12. A compound according to claim 11, wherein R⁵ is H, halo or (C₁-C₆)alkyl.
 13. A compound according to claim 1, selected from the group consisting of: (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)methanone; (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone; (2-Morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone; (4′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone; (5′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone; (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Fluoro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Ethyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-propyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-propyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Cyclopropyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Cyclopropyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Butyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Butyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Isobutyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Isobutyl-9-methyl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; [9-Methyl-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(5′-methyl-3,4,5,6-tetrahydro-2-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (4′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone; (5′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone; (4′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone; (5′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone; (3′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone; (4′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone; (5′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone; (9-Methyl-2-pyrrolidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-ethyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-cyclopropyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-cyclohexyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-piperidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; [9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; [9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (2-Benzyl-9-chloro-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone; (2-Ethyl-9-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-(9-methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone; (6′-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone; (6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[9-methyl-2-(tetrahydro-pyran-4-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-methanone; (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone; (9-Methyl-2-morpholin-4-yl-4,5-dihydro-3H-1,3,6-triaza-benzo[e]azulen-6-yl)-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone; (9-Chloro-2-ethyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone; (9-Chloro-2-propyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone; (9-Chloro-2-cyclopropyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone; (9-Chloro-2-cyclohexyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone; (9-Chloro-2-piperidin-1-yl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-phenyl-piperidin-4-yl)-methanone; [9-Chloro-2-(4-methyl-piperazin-1-yl)-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl]-(1-phenyl-piperidin-4-yl)-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-fluoro-phenyl)-piperidin-4-yl]-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(2-chloro-phenyl)-piperidin-4-yl]-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-chloro-phenyl)-piperidin-4-yl]-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-o-tolyl-piperidin-4-yl)-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-m-tolyl-piperidin-4-yl)-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(1-p-tolyl-piperidin-4-yl)-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-propyl-phenyl)-piperidin-4-yl]-methanone; (9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[1-(4-isopropyl-phenyl)-piperidin-4-yl]-methanone; (6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone; (6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-methanone; (3-Methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)-methanone; (3-Ethyl-6-fluoro-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3-tert-Butyl-6-fluoro-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3-Benzyl-6-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-phenyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-m-tolyl-piperidin-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-p-tolyl-piperidin-4-yl)-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-m-tolyl-piperidin-4-yl)-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(1-p-tolyl-piperidin-4-yl)-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone; (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone; (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-pyrazin-2-yl-piperidin-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone; (7-Fluoro-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (7-Fluoro-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone; (7-Methyl-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanone; (7-Methyl-5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-phenyl-piperidin-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-fluoro-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-fluoro-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-fluoro-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-chloro-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-chloro-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-o-tolyl-piperidin-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-m-tolyl-piperidin-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(1-p-tolyl-piperidin-4-yl)-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(2-methoxy-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-methoxy-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-ethyl-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-propyl-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-isopropyl-phenyl)-piperidin-4-yl]-methanone; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone; 3-[4-(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-piperidin-1-yl]-benzonitrile; (5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-[1-(3-nitro-phenyl)-piperidin-4-yl]-methanone; [1-(2-Amino-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone; [1-(4-Amino-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone; [1-(2-Aminomethyl-phenyl)-piperidin-4-yl]-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-methanone; and a pharmaceutically acceptable salt or solvate thereof.
 14. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
 15. The use of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease or condition mediated by vasopressin V_(1a) receptors.
 16. A method of treatment of a disease or condition mediated by vasopressin V_(1a) receptors comprising administration to a subject in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.
 17. The use of claim 15 or the method of claim 16 wherein the disease or condition mediated by vasopressin V_(1a) receptors is selected from dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea), pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.
 18. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 